New compounds

ABSTRACT

The present invention provides organic compounds of the following structure; A-L1-B—C-D-L2-E that are useful for treating or preventing conditions or disorders associated with DGAT1 activity in animals, particularly humans.

BACKGROUND OF THE INVENTION

Obesity can be viewed as an energy balance disorder, arising when energyinput exceeds energy output, with most of the excess calories convertedinto triglycerides and stored in the adipose tissue. Medicationscurrently approved for the treatment of obesity attempt to restoreenergy balance primarily by decreasing energy input by eithersuppressing appetite or interfering with lipid absorption in the smallintestine. Because of the rapid increase in the prevalence of obesityworldwide and the lack of efficacy of current medical therapies, novelpharmacologic therapies for obesity are required.

One potential therapeutic strategy involves inhibiting triglyceridesynthesis. Although triglycerides are essential for normal physiology,excess triglyceride accumulation results in obesity and, particularlywhen it occurs in nonadipose tissues, is associated with insulinresistance. DGAT is an enzyme that catalyzes the last step intriacylglycerol biosynthesis. DGAT catalyzes the coupling of a1,2-diacylglycerol with a fatty acyl-CoA resulting in Coenzyme A andtriacylglycerol. Two enzymes that display DGAT activity have beenidentified: DGAT1 (acyl coA-diacylglycerol acyl transferase 1, see Caseset al, Proc. Natl. Acad. Sci. 95:13018-13023, 1998) and DGAT2 (acylcoA-diacylglycerol acyl transferase 2, see Cases et al, J. Biol. Chem.276:38870-38876, 2001). DGAT1 and DGAT2 do not share significant proteinsequence homology. Importantly, DGAT1 knockout mice are protected fromhigh fat diet-induced weight gain and insulin resistance (Smith et al,Nature Genetics 25:87-90, 2000). The phenotype of the DGAT1 knockoutmice suggest that a DGAT1 inhibitor has utility for the treatment ofobesity and obesity-associated complications.

-   WO2006113919 discloses aryl alkyl acid derivatives having DGAT    inhibitory activity.-   WO2006044775 discloses biphenyl-4-yl-carbonylamino acid derivatives    having DGAT inhibitory activity.-   WO2006134317 discloses oxadiazole derivatives having DGAT inhibitor    activity.-   WO2006082952 discloses amide derivatives having DGAT inhibitor    activity.-   WO2006082010 discloses compounds having DGAT inhibitor activity.-   WO 2006/019020 A1 and WO 2006/004200 A1 disclose urea derivatives    having DGAT inhibitory activity.-   WO 2005/044250 A1 disclose sulfonamide compounds having DGAT    inhibitory activity.-   WO 2005/013907 A2 discloses pyrrolo[1,2-b] derivatives having DGAT    inhibitory activity.-   WO 2005/072740 A2 discloses compounds having DGAT inhibitory    activity.-   JP 2005/206492 A2 disloses sulfonamide compounds having DGAT    inhibitory activity.-   JP 2004/067635 A2 discloses phosphonic acid diesters having DGAT    inhibitory activity.-   US 2004/0224997 A1 discloses aryl alkyl acid derivatives having    DGAT1 inhibitory activity.-   WO 2004/04775 A2 discloses fused bicyclic nitrogen-containing    heterocycles having DGAT inhibitory activity.-   US 2005/0101660 A1 discloses dibenzo-p-dioxane derivatives having    DGAT inhibitory activity.-   EP 0573696 A1 discloses heterobiaryl derivatives of the general    structure R¹NH—X₁—X₂—X₃—Y₁—Y₁—Y₃—Y₄-E having aggregation inhibiting    activity.-   US 2005/0143422 A1 relates to biaryl sulfonamides and their use as    metalloproteinase inhibitors.-   WO 00/25780 relates to amine compounds of the general structure    X—N(R)—B-D and their use as IMPDH inhibitors.-   WO 01/42241 relates to substituted pyridazine compounds having    cytokine inhibitory activity.-   WO 02/055484 A1 relates to a compound of the general formula    R¹—X¹—Y—X²-A-B—X³—N(—X⁴—R²)—Z—Ar, wherein A and B represent 5- or    6-membered aromatic rings. The compound can be used as a blood lipid    depressant.-   WO 02/085891 A1 relates to 2,6-substituted chroman derivatives which    are useful in the treatment of beta-3 adrenoreceptor-mediated    conditions.-   WO 02/11724 A2 relates to pharmaceutical compositions comprising    2-pyridinamines which can be used for preventing ischemic cell    death.-   WO 03/062215 A1 relates to substituted thia-/oxa-/pyrazoles for    inhibiting the activity of one or more protein kinases.-   WO 2004/000788 A1 relates to ureido-substituted aniline compounds    which are useful as serine protease inhibitors.-   WO 2004/032882 A2 relates to oxazole derivatives which are useful in    the treatment of diseases associated with inappropriate protein    kinase activity.-   WO 2004/041810 A1 relates to nitrogen-containing heteroaryl    compounds which are useful for treatment of protein kinase mediated    disorders.-   WO 2004/046133 A1 relates to amino-heterocycles useful as VR-1    antagonists for treating pain.-   WO 2004/089286 A2 relates to nitrogen-containing heteroaryl    compounds which are useful for treating disorders associated with    abnormal tyrosine kinase activity.-   WO 2004/110350 A2 relates to compounds of the general structure    (A)-L_(A)-(B)-L_(B)-(C)-L_(C)-(D) wherein A, B, C and D represent    aryl/heteroaryl moieties. The compounds are useful for treating    neurodegenerative diseases.-   WO 2005/012295 A1 relates to substituted thiazole    benzoisothiazoledioxo derivatives which are useful for treating    diabetes.-   WO 2005/016862 A1 relates to substituted arylalkanoic acid    derivatives having prostaglandin production-suppressing activity.-   WO 2005/085227 A1 relates to pyridine compounds which are useful as    inhibitors of PKB/AKT kinase activity and in the treatment of cancer    and arthritis.-   WO 2005/100344 A1 relates to compounds which comprise substituted    pyridazine and pyrimidine moieties. These compounds are useful for    inhibiting the activity of a serine/threonine protein kinase.-   WO 2005/116003 A2 relates to substituted oxazolobenzoisothiazole    dioxide derivatives which are useful in the treatment of diabetes.-   WO 98/46574 relates to pyridazine and phthalazine derivatives which    are useful as. anticonvulsants.-   WO 99/24404 relates to substituted pyridine compounds which are    useful as anti-inflammatory agents.

BRIEF DESCRIPTION OF THE INVENTION

The present invention provides derivatives that are useful for treatingor preventing conditions or disorders associated with DGAT1 activity inanimals, particularly humans.

The compound provided by the present invention has the followingstructure

A-L1-B—C-D-L2-E

wherein

-   -   A is a substituted or unsubstituted alkyl, cycloalkyl, aryl, or        heterocyclyl group;    -   L1 is selected from the group consisting of:        -   an amine group —NH—        -   a substituted amine group of the formula —N(CH₃)—, —CH₂—NH—            or —CH₂—CH₂—NH—,        -   an amide group —C(O)—NH—,        -   a sulphonamide group —S(O)₂—NH—, or        -   a urea group —NHC(O)—NH—,    -   B is a substituted or unsubstituted, monocyclic, 5- or        6-membered divalent heteroaryl group,    -   C-D is selected from the following cyclic structures:        -   C-D together is a substituted or unsubstituted divalent            biphenyl group,        -   C is a substituted or unsubstituted divalent phenyl group            and D is a single bond,        -   C is a substituted or unsubstituted divalent phenyl group,            and D is a substituted or unsubstituted divalent            non-aromatic monocyclic ring which is selected from a            saturated or unsaturated divalent cycloalkyl group or a            saturated or unsaturated divalent heterocycloalkyl group,        -   C-D together is a Spiro residue, wherein            -   the first cyclic component is a benzo-fused cyclic                component wherein the ring which is fused to the phenyl                part is a 5- or 6-membered ring, optionally comprising                one or more heteroatoms, the first cyclic component                being attached to the moiety B via its phenyl part, and            -   the second cyclic component is a cycloalkyl or                cycloalkylidenyl residue which is attached to L2,    -   L2 is selected from the group consisting of:        -   a single bond,        -   a divalent residue having the following structure:

—[R¹]_(a)—[R²]_(b)—[C(O)]_(c)—[N(R³)_(d)—[R⁴]_(e)—[R⁵]_(f)—

-   -   -   wherein        -   a is 0 or 1,        -   b is 0 or 1,        -   c is 0 or 1,        -   d is 0 or 1,        -   e is 0 or 1,        -   f is 0 or 1,        -   with the provisos that (a+b+c+d+e+f)>0, and c=1 if d=1,        -   R¹, R², R⁴ and R⁵, which can be the same or different, are a            substituted or unsubstituted divalent alkyl, cycloalkyl,            alkenyl, alkynyl, alkylene, aryl or heterocyclyl residue,        -   R³ is H or hydrocarbyl, or R³ and R⁴ form together with the            nitrogen atom to which they are attached a 5- or 6-membered            heterocycloalkyl group,        -   with the proviso that R¹ and R² are not both alkyl if c=1            and d=e=f=0 and the carbonyl carbon atom is attached to the            moiety E,        -   an alkylidenyl group which is linked to the moiety D via a            double bond, and

    -   E is selected from the group consisting of:        -   a sulphonic acid group and derivatives thereof,        -   a carboxyl group and derivatives thereof, wherein the            carboxyl carbon atom is attached to L2,        -   a phosphonic acid group and derivatives thereof,        -   an alpha-keto hydroxyalkyl group,        -   a hydroxyalkyl group wherein the carbon atom bonded to the            hydroxyl group is further substituted with one or two            trifluoro-methyl groups,        -   a substituted or unsubstituted five-membered heterocyclyl            residue having in the ring at least two heteroatoms and at            least one carbon atom, wherein            -   at least one carbon atom of the ring is bonded to two                heteroatoms;            -   at least one of the heteroatoms to which the carbon atom                of the ring is bonded is a member of the ring;            -   and at least one of the heteroatoms to which the carbon                atom of the ring is bonded or at least one of the                heteroatoms of the ring is bearing a hydrogen atom;

    -   with the provisos that

    -   L2 is not a single bond or a divalent alkyl group if the moiety        D is a single bond,

    -   L2 is not a single bond if the moiety D is an unsubstituted        divalent phenyl group and E is a carboxylic acid or a derivative        thereof,

    -   E is not a carboxamide group if L2 comprises an amide group,

    -   E is not a —COON group if D is a single bond and L2 is a        —N(CH₃)—C(O)— group wherein the carbonyl carbon atom is attached        to the moiety E,

    -   L2 is not a divalent N-methyl piperidinyl group if the moiety E        is a pyridinyl-1,2,4-triazolyl group

    -   L2 is not —C(O)—[R⁴]_(e)—[R⁵]_(f)— when C is a substituted or        unsubstituted divalent phenyl group and D is a single bond.

Unless otherwise indicated, the compounds provided in the formula aboveare meant to include all pharmaceutically acceptable salts, prodrugs,stereoisomers, crystalline forms, or polymorphs thereof.

The present invention also provides pharmaceutical compositionscomprising the compound as defined above and a pharmaceuticallyacceptable carrier or excipient.

The present invention also provides methods for treating or preventingconditions or disorders associated with DGAT1 activity in animals,particularly humans.

Thus the present invention also provides a method for treating orpreventing conditions or disorders associated with DGAT1 activity inmammals which method comprises administering to a mammal in need thereofa therapeutically effective amount of a compound of the presentinvention. Preferably, the disorder is selected from the following:metabolic disorders such as obesity, diabetes, anorexia nervosa,bulimia, cachexia, syndrome X, insulin resistance, hypoglycemia,hyperglycemia, hyperuricemia, hyperinsulinemia, hypercholesterolemia,hyperlipidemia, dyslipidemia, mixed dyslipidemia, hypertriglyceridemia,and nonalcoholic fatty liver disease; cardiovascular diseases, such asatherosclerosis, arteriosclerosis, acute heart failure, congestive heartfailure, coronary artery disease, cardiomyopathy, myocardial infarction,angina pectoris, hypertension, hypotension, stroke, ischemia, ischemicreperfusion injury, aneurysm, restenosis, and vascular stenosis;neoplastic diseases, such as solid tumors, skin cancer, melanoma,lymphoma, and endothelial cancers, for example, breast cancer, lungcancer, colorectal cancer, stomach cancer, other cancers of thegastrointestinal tract (for example, esophageal cancer and pancreaticcancer), prostate cancer, kidney cancer, liver cancer, bladder cancer,cervical cancer, uterine cancer, testicular cancer, and ovarian cancer,dermatological conditions, such as acne vulgaris. In yet another aspect,the present invention provides methods of using a compound orcomposition of the invention as an anorectic.

The present invention also provides the use of a compound having thefollowing structure

A-L1-B—C-D-L2-E

-   -   wherein        -   A is a substituted or unsubstituted alkyl, cycloalkyl, aryl,            or heterocyclyl group,        -   L1 is selected from the group consisting of:            -   an amine group —NH—            -   a substituted amine group of the formula —N(CH₃)—,                —CH₂—NH— or —CH₂—CH₂—NH—,            -   an amide group —C(O)—NH—,            -   a sulphonamide group —S(O)₂—NH—, or            -   a urea —NHC(O)—NH—,        -   B is a substituted or unsubstituted, monocyclic, 5- or            6-membered divalent heteroaryl group,        -   C-D is selected from the following cyclic structures:            -   C-D together is a substituted or unsubstituted divalent                biphenyl group,            -   C is a substituted or unsubstituted divalent phenyl                group and D is a single bond,            -   C is a substituted or unsubstituted divalent phenyl                group, and D is a substituted or unsubstituted divalent                non-aromatic monocyclic ring which is selected from a                saturated or unsaturated divalent cycloalkyl group or a                saturated or unsaturated divalent heterocycloalkyl                group,            -   C-D together is a Spiro residue, wherein                -   the first cyclic component is a benzo-fused cyclic                    component wherein the ring which is fused to the                    phenyl part is a 5- or 6-membered ring, optionally                    comprising one or more heteroatoms, the first cyclic                    component being attached to the moiety B via its                    phenyl part, and                -   the second cyclic component is a cycloalkyl or                    cycloalkylidenyl residue which is attached to L2,        -   L2 is selected from the group consisting of:            -   a single bond,            -   a divalent residue having the following structure:

—[R¹]_(a)—[R²]_(b)—[C(O)]_(c)—[N(R³)]_(d)—[R⁴]_(e)—[R⁵]_(f)—

-   -   -   -   wherein            -   a is 0 or 1,            -   b is 0 or 1,            -   c is 0 or 1,            -   d is 0 or 1,            -   e is 0 or 1,            -   f is 0 or 1,            -   with the provisos that (a+b+c+d+e+f)>0, and c=1 if d=1,            -   R¹, R², R⁴ and R⁵, which can be the same or different,                are a substituted or unsubstituted divalent alkyl,                cycloalkyl, alkenyl, alkynyl, alkylene, aryl or                heterocyclyl residue,            -   R³ is H or hydrocarbyl, or R³ and R⁴ form together with                the nitrogen atom to which they are attached a 5- or                6-membered heterocycloalkyl group,            -   an alkylidenyl group which is linked to the moiety D via                a double bond, and

        -   E is selected from the group consisting of:            -   a sulphonic acid group and derivatives thereof,            -   a carboxyl group and derivatives thereof, wherein the                carboxyl carbon atom is attached to L2,            -   a phosphonic acid group and derivatives thereof,            -   an alpha-keto hydroxyalkyl group,            -   a hydroxyalkyl group wherein the carbon atom bonded to                the hydroxyl group is further substituted with one or                two trifluoro-methyl groups,            -   a substituted or unsubstituted five-membered                heterocyclyl residue having in the ring at least two                heteroatoms and at least one carbon atom, wherein                -   the at least one carbon atom of the ring is bonded                    to two heteroatoms;                -   at least one of the heteroatoms to which the carbon                    atom of the ring is bonded is a member of the ring;                -   and at least one of the heteroatoms to which the                    carbon atom of the ring is bonded or at least one of                    the heteroatoms of the ring is bearing a hydrogen                    atom;

    -   or a prodrug or a pharmaceutically acceptable salt thereof for        the manufacture of a medicament for the treatment of DGAT1        associated disorders.

The treatment of prevention of the DGAT1-related disorders or conditionslisted above consists of administering to subject in need thereof atherapeutically effective amount of a compound described in thisinvention. The treatment may also include co-administration withadditional therapeutic agents.

DETAILED DESCRIPTION OF THE INVENTION

Listed below are definitions of various terms used to describe thecompounds of the present invention. These definitions apply to the termsas they are used throughout the specification unless they are otherwiselimited in specific instances either individually or as part of a largergroup, e.g., wherein an attachment point of a certain group is limitedto a specific atom within that group.

The term “substituted or unsubstituted alkyl” refers to straight- orbranched-chain hydrocarbon groups having 1-20 carbon atoms, preferably1-10 carbon atoms, containing 0 to 3 substituents. Exemplaryunsubstituted alkyl groups include methyl, ethyl, propyl, isopropyl,n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl,4,4-dimethylpentyl, octyl and the like. Substituted alkyl groupsinclude, but are not limited to, alkyl groups substituted by one or moreof the following groups: halo, hydroxy, alkanoyl, alkoxy,alkoxycarbonyl, alkoxycarbonyloxy, alkanoyloxy, thiol, alkylthio,alkylthiono, alkylsulfonyl, sulfamoyl, sulfonamido, carbamoyl, cyano,carboxy, acyl, aryl, alkenyl, alkynyl, aralkyl, aralkanoyl, aralkylthio,arylsulfonyl, arylthio, aroyl, aroyloxy, aryloxycarbonyl, aralkoxy,guanidino, optionally substituted amino, heterocyclyl.

The term “lower alkyl” refers to those alkyl groups as described abovehaving 1-7, preferably 2-4 carbon atoms.

The term “halogen” or “halo” refers to fluorine, chlorine, bromine andiodine.

The term “alkenyl” refers to any of the above alkyl groups having atleast two carbon atoms and further containing a carbon to carbon doublebond at the point of attachment. Groups having 2-4 carbon atoms arepreferred.

The term “alkynyl” refers to any of the above alkyl groups having atleast two carbon atoms and further containing a carbon to carbon triplebond at the point of attachment. Groups having 2-4 carbon atoms arepreferred.

The term “alkylene” refers to a straight-chain bridge of 4-6 carbonatoms connected by single bonds, e.g., —(CH₂)x—, wherein x is 4-6, whichmay be interrupted with one or more heteroatoms selected from O, S,S(O), S(O)₂ or NR, wherein R may be hydrogen, alkyl, cycloalkyl, aryl,heterocyclyl, aralkyl, heteroaralkyl, acyl, carbamoyl, sulfonyl,alkoxycarbonyl, aryloxycarbonyl or aralkoxycarbonyl and the like; andthe alkylene may further be substituted with one or more substituentsselected from optionally substituted alkyl, cycloalkyl, aryl,heterocyclyl, oxo, halogen, hydroxy, carboxy, alkoxy, alkoxycarbonyl andthe like.

The term “cycloalkyl” refers to optionally substituted monocyclic,bicyclic or tricyclic hydrocarbon groups of 3-12 carbon atoms, each ofwhich may contain one or more carbon to carbon double bonds, or thecycloalkyl may be substituted by one or more substituents, such asalkyl, halo, oxo, hydroxy, alkoxy, alkanoyl, acylamino, carbamoyl,alkylamino, dialkylamino, thiol, alkylthio, cyano, carboxy,alkoxycarbonyl, sulfonyl, sulfonamido, sulfamoyl, heterocyclyl and thelike.

The term “carboxamide” refers to —C(O)—NHR_(α), wherein R_(α) isselected from hydrogen, a C₁-C₈ alkyl group, a cycloalkyl group, asubstituted or unsubstituted aryl group, a substituted or unsubstitutedheterocyclyl group, and carboxamide is preferably —C(O)—NH₂.

Exemplary monocyclic hydrocarbon groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl andcyclohexenyl and the like.

Exemplary bicyclic hydrocarbon groups include bornyl, indyl,hexahydroindyl, tetrahydronaphthyl, decahydronaphthyl,bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl,6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl,bicyclo[2.2.2]octyl and the like.

Exemplary tricyclic hydrocarbon groups include adamantyl and the like.

The term “alkoxy” refers to alkyl-O—.

The term “alkanoyl” refers to alkyl-C(O)—.

The term “alkanoyloxy” refers to alkyl-C(O)—O—.

The terms “alkylamino” and “dialkylamino” refer to alkyl-NH— and(alkyl)₂N—, respectively.

The term “alkanoylamino” refers to alkyl-C(O)—NH—.

The term “alkylthio” refers to alkyl-S—.

The term “alkylthiono” refers to alkyl-S(O)—.

The term “alkylsulfonyl” refers to alkyl-S(O)₂—.

The term “alkoxycarbonyl” refers to alkyl-O—C(O)—.

The term “alkoxycarbonyloxy” refers to alkyl-O—C(O)O—.

The term “carbamoyl” refers to H₂NC(O)—, alkyl-NHC(O)—, (alkyl)₂NC(O)—,aryl-NHC(O)—, alkyl(aryl)-NC(O)—, heteroaryl-NHC(O)—,alkyl(heteroaryl)-NC(O)—, aralkyl-NHC(O)—, alkyl(aralkyl)-NC(O)— and thelike.

The term “sulfamoyl” refers to H₂NS(O)₂—, alkyl-NHS(O)₂,(alkyl)₂NS(O)₂—, aryl-NHS(O)₂, alkyl(aryl)-NS(O)₂—, (aryl)₂NS(O)₂—,heteroaryl-NHS(O)₂—, aralkyl-NHS(O)₂—, heteroaralkyl-NHS(O)₂— and thelike.

The term “sulfonamido” refers to alkyl-S(O)₂—NH—, aryl-S(O)₂—NH—,aralkyl-S(O)₂—NH—, heteroaryl-S(O)₂—NH—, heteroaralkyl-S(O)₂—NH—,alkyl-S(O)₂—N(alkyl)-, aryl-S(O)₂—N(alkyl)-, aralkyl-S(O)₂—N(alkyl)-,heteroaryl-S(O)₂—N(alkyl)-, heteroaralkyl-S(O)₂—N(alkyl)- and the like.

The term “sulfonyl” refers to alkylsulfonyl, arylsulfonyl,heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl and the like.

The term “optionally substituted amino” refers to a primary or secondaryamino group which may optionally be substituted by a substituent such asacyl, sulfonyl, alkoxycarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl,heteroaryloxycarbonyl, aralkoxycarbonyl, heteroaralkoxycarbonyl,carbamoyl and the like.

The term “aryl” refers to monocyclic or bicyclic aromatic hydrocarbongroups having 6-12 carbon atoms in the ring portion, such as phenyl,biphenyl, naphthyl and tetrahydronaphthyl, each of which may optionallybe substituted by 1-4 substituents, such as optionally substitutedalkyl, trifluoromethyl, cycloalkyl, halo, hydroxy, alkoxy, acyl,alkanoyloxy, aryloxy, optionally substituted amino, thiol, alkylthio,arylthio, nitro, cyano, carboxy, alkoxycarbonyl, carbamoyl, alkylthiono,sulfonyl, sulfonamido, heterocyclyl and the like.

The term “monocyclic aryl” refers to optionally substituted phenyl asdescribed under aryl.

The term “aralkyl” refers to an aryl group bonded directly through analkyl group, such as benzyl.

The term “aralkanoyl” refers to aralkyl-C(O)—.

The term “aralkylthio” refers to aralkyl-S—.

The term “aralkoxy” refers to an aryl group bonded directly through analkoxy group.

The term “arylsulfonyl” refers to aryl-S(O)₂—.

The term “arylthio” refers to aryl-S—.

The term “aroyl” refers to aryl-C(O)—.

The term “aroyloxy” refers to aryl-C(O)—O—.

The term “aroylamino” refers to aryl-C(O)—NH—.

The term “aryloxycarbonyl” refers to aryl-O—C(O)—.

The term “heterocyclyl” or “heterocyclo” refers to an optionallysubstituted, fully saturated or unsaturated, aromatic or nonaromaticcyclic group, e.g., which is a 4- to 7-membered monocyclic, 7- to12-membered bicyclic or 10- to 15-membered tricyclic ring system, whichhas at least one heteroatom in at least one carbon atom-containing ring.Each ring of the heterocyclic group containing a heteroatom may have 1,2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfuratoms, where the nitrogen and sulfur heteroatoms may also optionally beoxidized. The heterocyclic group may be attached at a heteroatom or acarbon atom.

Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl,pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl,imidazolidinyl, triazolyl, oxazolyl, oxazolidinyl, isoxazolinyl,isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl,isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl,piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridyl,pyridyl N-oxide, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl,morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinylsulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl,1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl and the like.

Exemplary bicyclic heterocyclic groups include indolyl, dihydroidolyl,benzothiazolyl, benzoxazinyl, benzoxazolyl, benzothienyl,benzothiazinyl, quinuclidinyl, quinolinyl, tetrahydroquinolinyl,decahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl,decahydroisoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl,benzofuryl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl,quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such asfuro[2,3-c]pyridinyl, furo[3,2-b]-pyridinyl] or furo[2,3-b]pyridinyl),dihydroisoindolyl, 1,3-dioxo-1,3-dihydroisoindol-2-yl,dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl),phthalazinyl and the like.

Exemplary tricyclic heterocyclic groups include carbazolyl,dibenzoazepinyl, dithienoazepinyl, benzindolyl, phenanthrolinyl,acridinyl, phenanthridinyl, phenoxazinyl, phenothiazinyl, xanthenyl,carbolinyl and the like.

The term “heterocyclyl” includes substituted heterocyclic groups.Substituted heterocyclic groups refer to heterocyclic groups substitutedwith 1, 2 or 3 substituents. Exemplary substituents include, but are notlimited to, the following:

-   -   (a) optionally substituted alkyl;    -   (b) hydroxyl (or protected hydroxyl);    -   (c) halo;    -   (d) oxo, i.e., ═O;    -   (e) optionally substituted amino;    -   (f) alkoxy;    -   (g) cycloalkyl;    -   (h) carboxy;    -   (i) heterocyclooxy;    -   (j) alkoxycarbonyl, such as unsubstituted lower alkoxycarbonyl;    -   (k) mercapto;    -   (l) nitro;    -   (m) cyano;    -   (n) sulfamoyl;    -   (o) alkanoyloxy;    -   (p) aroyloxy;    -   (q) arylthio;    -   (r) aryloxy;    -   (s) alkylthio;    -   (t) formyl;    -   (u) carbamoyl;    -   (v) aralkyl; or    -   (w) aryl optionally substituted with alkyl, cycloalkyl, alkoxy,        hydroxyl, amino, acylamino, alkylamino, dialkylamino or halo.

The term “heterocyclooxy” denotes a heterocyclic group bonded through anoxygen bridge.

The terms “saturated or unsaturated heterocycloalkyl” or“heterocycloalkyl” refers to nonaromatic heterocyclic or heterocyclylgroups as described above.

The term “heteroaryl” refers to an aromatic heterocycle, e.g.,monocyclic or bicyclic aryl, such as pyrrolyl, pyrazolyl, imidazolyl,triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl,thienyl, pyridyl, pyridyl N-oxide, pyrazinyl, pyrimidinyl, pyridazinyl,indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl,isoquinolinyl, benzimidazolyl, benzofuryl and the like, optionallysubstituted by, e.g.; lower alkyl, lower alkoxy or halo.

The term “heteroarylsulfonyl” refers to heteroaryl-S(O)₂—.

The term “heteroaroyl” refers to heteroaryl-C(O)—.

The term “heteroaroylamino” refers to heteroaryl-C(O)NH—.

The term “heteroaralkyl” refers to a heteroaryl group bonded through analkyl group.

The term “heteroaralkanoyl” refers to heteroaralkyl-C(O)—.

The term “heteroaralkanoylamino” refers to heteroaralkyl-C(O)NH—.

The term “acyl” refers to alkanoyl, aroyl, heteroaroyl, aralkanoyl,heteroaralkanoyl and the like.

The term “acylamino” refers to alkanoylamino, aroylamino;heteroaroylamino, aralkanoylamino, heteroaralkanoylamino and the like.

The term “divalent” refers to a residue linked to at least two residuesand optionally having further substituents. As an example, within thecontext of the present invention the expression “substituted orunsubstituted divalent phenyl residue” is considered to be equivalent tothe expression “substituted or unsubstituted phenylene residue”.

The present invention provides a compound having the following structure

A-L1 -B—C-D-L2-E

-   -   and pharmaceutically acceptable salts, and prodrugs thereof,        wherein        -   A is a substituted or unsubstituted alkyl, cycloalkyl, aryl,            or heterocyclyl group,        -   L1 is selected from the group consisting of:            -   an amine group —NH—            -   a substituted amine group of the formula —N(CH₃)—,                —CH₂—NH— or —CH₂—CH₂—NH—,            -   an amide group —C(O)—NH—,            -   a sulphonamide group —S(O)₂—NH—, or            -   a urea group —NHC(O)—NH—,        -   B is a substituted or unsubstituted, monocyclic, 5- or            6-membered divalent heteroaryl group,        -   C-D is selected from the following cyclic structures:            -   C-D together is a substituted or unsubstituted divalent                biphenyl group,            -   C is a substituted or unsubstituted divalent phenyl                group and D is a single bond,            -   C is a substituted or unsubstituted divalent phenyl                group, and D is a substituted or unsubstituted divalent                non-aromatic monocyclic ring which is selected from a                saturated or unsaturated divalent cycloalkyl group or a                saturated or unsaturated divalent heterocycloalkyl                group,            -   C-D together is a Spiro residue, wherein                -   the first cyclic component is a benzo-fused cyclic                    component wherein the ring which is fused to the                    phenyl part is a 5- or 6-membered ring, optionally                    comprising one or more heteroatoms, the first cyclic                    component being attached to the moiety B via its                    phenyl part, and                -   the second cyclic component is a cycloalkyl or                    cycloalkylidenyl residue which is attached to L2,        -   L2 is selected from the group consisting of:            -   a single bond,            -   a divalent residue having the following structure:

—[R¹]_(a)—[R²]_(b)—[C(O)]_(c)—[N(R³)]_(d)—R⁴]_(e)—[R⁵]_(f)—

-   -   -   -   wherein            -   a is 0 or 1,            -   b is 0 or 1,            -   c is 0 or 1,            -   d is 0 or 1,            -   e is 0 or 1,            -   f is 0 or 1,            -   with the provisos that (a+b+c+d+e+f)>0, and c=1 if d=1,            -   R¹, R², R⁴ and R⁵, which can be the same or different,                are a substituted or unsubstituted divalent alkyl,                cycloalkyl, alkenyl, alkynyl, alkylene, aryl or                heterocyclyl residue,            -   R³ is H or hydrocarbyl, or R³ and R⁴ form together with                the nitrogen atom to which they are attached a 5- or                6-membered heterocycloalkyl group,            -   with the proviso that R¹ and R² are not both alkyl if                c=1 and d=e=f=0 and the carbonyl carbon atom is attached                to the moiety E,            -   an alkylidenyl group which is linked to the moiety D via                a double bond, and

        -   E is selected from the group consisting of:            -   a sulphonic acid group and derivatives thereof,            -   a carboxyl group and derivatives thereof, wherein the                carboxyl carbon atom is attached to L2,            -   a phosphonic acid group and derivatives thereof,            -   an alpha-keto hydroxyalkyl group,            -   a hydroxyalkyl group wherein the carbon atom bonded to                the hydroxyl group is further substituted with one or                two trifluoro-methyl groups,            -   a substituted or unsubstituted five-membered                heterocyclyl residue having in the ring at least two                heteroatoms and at least one carbon atom, wherein            -   the at least one carbon atom of the ring is bonded to                two heteroatoms;            -   at least one of the heteroatoms to which the carbon atom                of the ring is bonded is a member of the ring;            -   and at least one of the heteroatoms to which the carbon                atom of the ring is bonded or at least one of the                heteroatoms of the ring is bearing a hydrogen atom;

        -   with the provisos that

        -   L2 is not a single bond or a divalent alkyl group if the            moiety D is a single bond,

        -   L2 is not a single bond if the moiety D is an unsubstituted            divalent phenyl group and E is a carboxylic acid or a            derivative thereof,

        -   E is not a carboxamide group if L2 comprises an amide group,

        -   E is not a —COOH group if D is a single bond and L2 is a            —N(CH₃)—C(O)— group wherein the carbonyl carbon atom is            attached to the moiety E,

        -   L2 is not a divalent N-methyl piperidinyl group if the            moiety E is a pyridinyl-1,2,4-triazolyl group.

The present invention provides a compound having the following structure

A-L1-B—C-D-L2-E

-   -   and pharmaceutically acceptable salts, and prodrugs thereof,        wherein        -   A is a substituted or unsubstituted alkyl, cycloalkyl, aryl,            or heterocyclyl group,        -   L1 is selected from the group consisting of:            -   an amine group —NH—            -   a substituted amine group of the formula —N(CH₃)—,                —CH₂—NH— or —CH₂—CH₂—NH—,            -   an amide group —C(O)—NH—, 'a sulphonamide group                —S(O)₂—NH—, or            -   a urea group —NHC(O)—NH—,        -   B is a substituted or unsubstituted, monocyclic, 5- or            6-membered divalent heteroaryl group,        -   C-D is selected from the following cyclic structures:            -   C-D together is a substituted or unsubstituted divalent                biphenyl group,            -   C is a substituted or unsubstituted divalent phenyl                group and D is a single bond,            -   C is a substituted or unsubstituted divalent phenyl                group, and D is a substituted or unsubstituted divalent                non-aromatic monocyclic ring which is selected from a                saturated or unsaturated divalent cycloalkyl group or a                saturated or unsaturated divalent heterocycloalkyl                group,            -   C-D together is a spiro residue, wherein                -   the first cyclic component is a benzo-fused cyclic                    component wherein the ring which is fused to the                    phenyl part is a 5- or 6-membered ring, optionally                    comprising one or more heteroatoms, the first cyclic                    component being attached to the moiety B via its                    phenyl part, and                -   the second cyclic component is a cycloalkyl or                    cycloalkylidenyl residue which is attached to L2,        -   L2 is selected from the group consisting of:            -   a single bond,            -   a divalent residue having the following structure:

—[R¹]_(a)—[R²]_(b)]—[C(O)]_(c)—[N(R³)]_(d)—[R⁴]_(e)—[R⁵]_(f)—

-   -   -   -   wherein            -   a is 0 or 1,            -   b is 0 or 1,            -   c is 0 or 1,            -   d is 0 or 1,            -   e is 0 or 1,            -   f is 0 or 1,            -   with the provisos that (a+b+c+d+e+f)>0, and c=1 if d=1,            -   R¹, R², R⁴ and R⁵, which can be the same or different,                are “a substituted or unsubstituted divalent alkyl,                cycloalkyl, alkenyl, alkynyl, alkylene, aryl or                heterocyclyl residue,            -   R³ is H or hydrocarbyl, or R³ and R⁴ form together with                the nitrogen atom to which they are attached a 5- or                6-membered heterocycloalkyl group,            -   with the proviso that R¹ and R² are not both alkyl if                c=1 and d=e=f=0 and the carbonyl carbon atom is attached                to the moiety E,            -   an alkylidenyl group which is linked to the moiety D via                a double bond, and

        -   E is selected from the group consisting of:            -   a sulphonic acid group and derivatives thereof,            -   a carboxyl group and derivatives thereof, wherein the                carboxyl carbon atom is attached to L2,            -   a phosphonic acid group and derivatives thereof,            -   an alpha-keto hydroxyalkyl group,            -   a hydroxyalkyl group wherein the carbon atom bonded to                the hydroxyl group is further substituted with one or                two trifluoro-methyl groups,            -   a substituted or unsubstituted five-membered                heterocyclyl residue having in the ring at least two                heteroatoms and at least one carbon atom, wherein            -   the at least one carbon atom of the ring is bonded to                two heteroatoms;            -   at least one of the heteroatoms to which the carbon atom                of the ring is bonded is a member of the ring;            -   and at least one of the heteroatoms to which the carbon                atom of the ring is bonded or at least one of the                heteroatoms of the ring is bearing a hydrogen atom;

        -   with the provisos that

        -   L2 is not a single bond or a divalent alkyl group if the            moiety D is a single bond,

        -   L2 is not a single bond if the moiety D is an unsubstituted            divalent phenyl group and E is a carboxylic acid or a            derivative thereof,

        -   E is not a carboxamide group if L2 comprises an amide group,

        -   E is not a —COOH group if D is a single bond and L2 is a            —N(CH₃)—C(O)— group wherein the carbonyl carbon atom is            attached to the moiety E,

        -   L2 is not a divalent N-methyl piperidinyl group if the            moiety E is a pyridinyl-1,2,4-triazolyl group,

        -   L2 is not —C(O)—[R⁴]_(e)—[R⁵]_(f)— when C is a substituted            or unsubstituted divalent phenyl group and D is a single            bond.

Unless otherwise indicated, the compounds provided in the formula aboveare meant to include all pharmaceutically acceptable salts, prodrugs,stereoisomers, crystalline forms, or polymorphs thereof.

In a preferred embodiment, the moiety A is selected from the groupconsisting of a substituted or unsubstituted phenyl group and asubstituted or unsubstituted monocyclic or bicyclic heterocyclyl group.Preferred substituents are halogen, alkyl, cycloalkyl, cyano,trifluoromethyl, alkoxy, hydroxyl, optionally substituted amino, acyl,alkanoyloxy, alkanoylamino, aryloxy, alkylthio, arylthio, nitro,carboxy, alkoxycarbonyl, carbamoyl, alkylthiono, sulfonyl, sulfonamido,and heterocyclyl. More preferably, the substituents of moiety A areselected from halogen, alkyl, cycloalkyl, cyano, trifluoromethyl,alkoxy, alkanoylamino, hydroxyl, optionally substituted amino. Orpreferably, the substituents of moiety A are selected from halogen,lower alkyl, C3 to C6 cycloalkyl, cyano, trifluoromethyl, lower alkoxy,lower alkanoylamino, hydroxyl, optionally substituted amino.

When the moiety A is a monocyclic heterocyclyl, it is in a firstpreferred embodiment heteroaryl.

When the moiety A is a monocyclic heteroaryl, it preferably is apyridine, oxadiazole, pyridine N-oxide, pyrazole, isoxazole, pyridazine,pyrimidine or pyrazine residue.

When the moiety A is a bicyclic heterocyclyl, it preferably is abenzimidazole, benzoxazole, benzothiazole, oxazolopyridine,thiazolopyridine, imidazolopyridine, indole, quinoline, isoquinoline,benzofuran, benzothiophene, indazole, cinnoline, quinazoline,quinoxaline or phthalazine residue. More preferably, the bicyclicheterocyclyl group is selected from a benzimidazole, benzoxazole,benzothiazole, oxazolopyridine, thiazolopyridine or imidazolopyridinegroup.

When the moiety A is a cycloalkyl group, it is preferably a cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl group.

In a preferred embodiment, the linker moiety L1 is attached to the ringof the bicyclic heteroaryl group containing the heteroatom.

In a preferred embodiement L1 group is an amine group —NH—.

In another preferred embodiement L1 group is an amide group —C(O)NH— or—NHC(O)—

The amide group representing L1 can have the following orientations:

A←C(O)—NH→B or A←NH—C(O)→B

However, in a preferred embodiment the carbonyl carbon atom is attachedto the moiety A.

The substituted amine group —CH₂—NH— or —CH₂—CH₂—NH— representing L1 canbe attached to the moiety B either via the nitrogen atom or via thecarbon atom. However, in a preferred embodiment the carbon atom isattached to the moiety A.

The sulphonamide group representing L1 can have the followingorientations:

A←S(O)₂—NH→B or A←NH—S(O)₂→B

However, in a preferred embodiment the sulphur atom is attached to themoiety A.

According to the present invention, the moiety B is a substituted orunsubstituted, monocyclic, 5- or 6-membered heteroaryl group. Asexplained above, the term “divalent” refers to a residue being attachedto at least two further residues. Within the context of the presentinvention, the expression “unsubstituted or substituted monocyclic 5- or6-membered heteroarenediyl group” is considered to be equivalent to theexpression used above.

Besides the moieties L1 and C-D to which it is attached, the moiety Bcan have from 1 to 3 additional substituents. Preferred substituentscomprise halogen, alkyl, cycloalkyl, cyano, trifluoromethyl, alkoxy,hydroxyl, and optionally substituted amino.

Preferably, the moiety B is selected from the group consisting of a6-membered substituted or unsubstituted divalent heteroaryl groupwherein the heteroatom is nitrogen, or a 5-membered substituted orunsubstituted divalent heteroaryl group wherein the heteroatom isnitrogen, oxygen and/or sulphur.

In a preferred embodiment, the moiety B is selected from a pyridine,pyridine N-oxide, pyridazine, pyrimidine, pyrazine, oxazole, or thiazolegroup.

According to the present invention, the moiety C within the structuralelement C-D is a divalent phenyl group. As discussed above, theexpressions “phenylene” or “benzenediyl” are considered to beequivalent.

The divalent phenyl residue can be unsubstituted or can have from 1 to 4substituents. Preferred substituents comprise halogen, alkyl,cycloalkyl, cyano, trifluoromethyl, alkoxy, hydroxyl, and amino which isoptionally substituted.

When the structural element C-D is a divalent biphenyl group, the phenylmoiety D can be substituted or unsubstituted. Preferred substituents arethose listed above for moiety C.

When the moiety D is a substituted or unsubstituted divalentnon-aromatic monocyclic ring which is selected from a saturated orunsaturated divalent cycloalkyl group or a saturated or unsaturateddivalent heterocycloalkyl group, it is preferably selected from asubstituted or unsubstituted divalent cyclohexyl group or a non-aromatic6-membered substituted or unsubstituted divalent heterocycloalkyl groupwherein the heteroatom is nitrogen.

In a preferred embodiment, the 6-membered heterocycloalkyl group isselected from a piperidine group or a tetrahydro-pyridine group.

Preferred substituents of the divalent non-aromatic monocyclic ring arethose listed above for the moiety C.

When the moiety D is a substituted or unsubstituted divalentnon-aromatic monocyclic ring, especially a cyclohexyl, the moietyA-L1-B—C— and the moiety -L2-E are in a trans configuration e.g.

When the structural element C-D is a Spiro residue, the first cycliccomponent of the spiro residue is preferably selected from an indanylgroup, a benzo-tetrahydrofuranyl group, a benzo-pyrrolidinyl group, abenzo-pyrrolidinonyl group, or a benzo-piperidinyl group.

The second cyclic component of the spiro residue is preferably selectedfrom a cyclohexyl group or a cyclohexylidenyl group.

Preferred spiro residues can be those given below:

In other preferred embodiments, the second cyclic component can be acyclohexylidenyl group as shown below:

When the second cyclic component of the Spiro residue is acycloalkylidenyl group, the moiety L2 preferably is ═CH—.

When the moiety L2 is a divalent residue—[R¹]_(a)—[R²]_(b)—[(C(O)]_(c)—[N(R³)]_(d)—[R⁴]_(e)—[R⁵]_(f)—, it ispreferably selected from the group consisting of:

-   -   a divalent alkyl group having from 1 to 4 carbon atoms,    -   a divalent alkenyl group having from 2 to 3 carbon atoms,    -   a —C(O)— group,    -   a —C(O)—[R⁴]_(a)—R⁵— group wherein        -   e is 0 and R⁵ is selected from the group consisting of a            divalent substituted or unsubstituted C₁-C₄ alkyl group,            C₄-C₈ cycloalkyl group, phenyl group or 5- or 6-membered            heterocyclyl group, or        -   e is 1, R⁴ is a divalent substituted or unsubstituted C₁-C₄            alkyl group, and R⁵ is a divalent substituted or            unsubstituted C₄-C₈ cycloalkyl group, phenyl group or 5- or            6-membered heterocyclyl group,    -   a —R¹—R²— group, wherein R¹ is a divalent substituted or        unsubstituted C₁-C₄ alkyl group and R² is a divalent substituted        or unsubstituted C₄-C₈ cycloalkyl group, phenyl group or 5- or        6-membered heterocyclyl group,    -   a —C(O)—NH— group,    -   a —(CH₂)₁₋₃—C(O)—NH—(CH₂)₁₋₃-group    -   a —C(O)—NH—R⁴— group, wherein R⁴ is selected from a divalent        substituted or unsubstituted C₁₋₇ alkyl group, cyclohexyl group        or cyclopentyl group,    -   a —C(O)—N(R³)—R⁴— group, wherein R³ and R⁴ and the N-atom        together form a pyrrolidine ring or a piperidine ring.

Preferred substituents for residues R¹, R², R⁴ and R⁵ include hydroxyl,alkoxy, keto, amino which is optionally substituted, and alkyl.

Preferably, the divalent residue—[R¹]_(a)—[R²]_(b)—[C(O)]_(c)—[N(R³)]_(d)—[R⁴]_(e)—[R⁵]_(f)— has thefollowing orientation:

C-D←[R¹]_(a)—[R²]_(b)—[C(O)]_(c)—[N(R³)]_(d)—[R⁵]_(f)→E

When E is a carboxyl group or a derivative thereof, it is preferablyselected from a —COOH group, a carboxylic ester group, or a carboxamidegroup.

Chemical formulas of preferred carboxyl group derivatives are givenbelow:

For the carboxyl group derivatives above, “R—PRO” refers to the commonester derivatives that can serve as a prodrug.

Prodrug derivatives of any compound of the invention are derivatives ofsaid compounds which following administration release the parentcompound in vivo via some chemical or physiological process, e.g., aprodrug on being brought to the physiological pH or through enzymeaction is converted to the parent compound. Preferred arepharmaceutically acceptable ester derivatives convertible by solvolysisunder physiological conditions to the parent carboxylic acid, e.g.,lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzylesters; mono- or di-substituted lower alkyl esters, such as theω-(amino, mono- or di-lower alkylamino, carboxy, loweralkoxycarbonyl)-lower alkyl esters, the α-(lower alkanoyloxy, loweralkoxycarbonyl or di-lower alkylaminocarbonyl)-lower alkyl esters, suchas the pivaloyloxymethyl ester and the like conventionally used in theart.

When E is a sulphonic acid group or a derivative thereof, it ispreferably selected from a —S(O)₂—OH group, or a —S(O)₂—NHR⁶ group,wherein R⁶ is selected from hydrogen, a C₁-C₈ alkyl group, a cycloalkylgroup, a substituted or unsubstituted aryl group, a substituted orunsubstituted heterocyclyl group, or a carboxylic acid ester group.

The sulphonic acid group or derivative thereof can be attached to themoiety L2 via its sulphur atom or via its nitrogen atom. Preferably, itis attached to the moiety L2 via its sulphur atom.

Chemical formulas of preferred embodiments are also shown below:

wherein R has the same meaning as R⁶ defined above.

When E is an alpha-keto hydroxyalkyl group, the carbon atom bearing thehydroxyl group can be further substituted. Preferred substitutents arealkyl, cycloalkyl, aryl or heteroaryl. In a preferred embodiment, thehydroxyl-bearing carbon atom is having two substituents which are joinedtogether to form a substituted or unsubstituted cycloalkyl, aryl orheteroaryl group.

A chemical formula of a preferred embodiment is also shown below:

wherein R and R′ are independently hydrogen, alkyl, cycloalkyl, aryl orheteroaryl, or both residues R and R′ are joined together to form asubstituted or unsubstituted cycloalkyl or heterocycloalkyl group.

When E is a hydroxyalkyl group wherein the carbon atom bonded to thehydroxyl group is further substituted with one or two trifluoromethylgroups, preferred embodiments can have a structure as shown below:

When E is a substituted or unsubstituted 5-membered heterocyclylresidue, it is preferably selected from the group consisting of:

-   -   a tetrazole residue,    -   a triazole residue,    -   an oxadiazole residue,    -   a thiadiazole residue,    -   a diazole residue,    -   an oxazole residue,    -   a thiazole residue,    -   an oxathiadiazole residue,        the heterocyclyl residue optionally having one or more        substituents selected from an oxo group, a hydroxyl group and/or        a thiol group.

Chemical formulas of preferred heterocyclyl residues representing moietyE are also shown below:

In a further embodiement, the present invention concerns compounds offormula;

respectively designated as the SIGMA group and the SIGMA′ group, whereinthe moieties A, L1, B and -L2-E are the same as the preferred moietiesdescribed herein above for the structure A-L1-B—C-D-L2-E.

Preferred are the compounds in the SIGMA and SIGMA′ groups wherein;

-   -   the moiety B is selected from the group consisting of: a        substituted or unsubstituted pyridine group, a substituted or        unsubstituted pyridazine group, a substituted or unsubstituted        pyrimidine group, a substituted or unsubstituted pyrazine group,        a substituted or unsubstituted oxazole group,    -   the L1 group is selected from the group consisting of: an amine        group —NH—, an amide group —C(O)NH— or —NHC(O)— group,    -   the moiety A is a substituted or unsubstituted cycloalkyl, a        substituted or unsubstituted aryl, or a substituted or        unsubstituted heterocyclyl group, and is preferably selected        from the group consiting of a substituted or unsubstituted        phenyl, a substituted or unsubstituted pyridine, a substituted        or unsubstituted cyclohexyl, a substituted or unsubstituted        isoxazole, a substituted or unsubstituted oxadiazole, or a        substituted or unsubstituted pyrazole,    -   the moiety -L2- i.e. the divalent residue        —[(R¹]_(a)—[R²]_(b)—[C(O)]_(c)—[N(R³)]_(d)—[R⁴]_(e)—[R⁵]_(f)— is        selected from the group consisting of:        -   a divalent alkyl group having from 1 to 4 carbon atoms        -   a divalent alkenyl group having from 2 to 3 carbon atoms        -   a —C(O)— group        -   a —C(O)—[R⁴]_(e)—R⁵— group wherein        -   e is 0 and R⁵ is selected from the group consisting of a            divalent substituted or unsubstituted C₁-C₄ alkyl group,            C₄-C₈ cycloalkyl group, phenyl group or 5- or 6-membered            heterocyclyl group, or        -   e is 1, R⁴ is a divalent substituted or unsubstituted C₁-C₄            alkyl group, and R⁵ is a divalent substituted or            unsubstituted C₄-C₈ cycloalkyl cycloalkyl group, phenyl            group or 5- or 6-membered heterocyclyl group,        -   a —R¹—R²— group, wherein R¹ is a divalent substituted or            unsubstituted C₁-C₄ alkyl group and R² is a divalent            substituted or unsubstituted C₄-C₈ cycloalkyl group, phenyl            group or 5- or 6-membered heterocyclyl group,    -   a —C(O)—NH— group,    -   a —(CH₂)₁₋₃—C(O)—NH—(CH₂)₁₋₃— group,    -   a —C(O)—NH—R⁴— group, wherein R⁴ is selected from a divalent        substituted or unsubstituted C₁₋₇ alkyl group, cyclohexyl group        or cyclopentyl group,    -   a —C(O)—N(R³)—R⁴— group, wherein R³ and R⁴ and the N-atom        together form a pyrrolidine ring or a piperidine ring,    -   the moiety E is selected from the group consiting of:        -   —COOH,        -   a carbocylic ester group,        -   a carboxamide group,        -   a —S(O)₂—OH group,        -   a —S(O)₂—NHR⁶ group, wherein R⁶ is selected from hydrogen, a            C₁-C₈ alkyl group, a cycloalkyl group, a substituted or            unsubstituted aryl group, a substituted or unsubstituted            heterocyclyl group, or a carboxylic acid ester group,            or pharmaceutically acceptable salts, prodrugs,            stereoisomers, crystalline forms, or polymorphs thereof.

The invention covers the compounds in the SIGMA and SIGMA′ groupswherein the moiety -L2-E is equivalent to the below described groups E′.

Preferred are the compounds of formula;

respectively designated as the ALPHA group and the ALPHA′ group, or thecompounds of formula

respectively designated as the BETA group and the BETA′ group, or thecompounds of formula

respectively designated as the GAMMA group and the GAMMA′ group, or thecompounds of formula

respectively designated as the DELTA group and the DELTA′ group,or the compounds of formula

respectively designated as the EPSILON group and the EPSILON′ group, orthe compounds of formula

respectively designated as the THETA group and the THETA′ group, or thecompounds of formula

respectively designated as the KAPPA group and the KAPPA′ group, or thecompounds of formula

respectively designated as the ZETA group and the ZETA′ group, wherein;

-   -   A is a substituted or unsubstituted cycloalkyl, a substituted or        unsubstituted aryl, or a substituted or unsubstituted        heterocyclyl group,    -   E′ is -L2-E,        or pharmaceutically acceptable salts, prodrugs, stereoisomers,        crystalline forms, or polymorphs thereof.

Preferred are the compounds in the ALPHA, ALPHA′, BETA, BETA′, GAMMA,GAMMA′, DELTA, DELTA′, EPSILON, EPSILON′, THETA, THETA′, KAPPA, KAPPA′,ZETA, ZETA′ groups wherein the moieties A and moieties -L2-E are thesame as the preferred moieties described herein above for the structureA-L1-B—C-D-L2-E.

Preferred are the compounds in the ALPHA, ALPHA′, BETA, BETA′, GAMMA,GAMMA′, DELTA, DELTA′, EPSILON, EPSILON′, THETA, THETA′, KAPPA, KAPPA′,ZETA, ZETA′ groups wherein;

-   -   the moiety -L2- i.e. the divalent residue        —[R¹]_(a)—[R²]_(b)—[C(O)]_(c)—[N(R³)]_(d)—[R⁴]_(e)—[R⁵]_(f)— is        selected from the group consisting of:        -   a divalent alkyl group having from 1 to 4 carbon atoms        -   a divalent alkenyl group having from 2 to 3 carbon atoms        -   a —C(O)— group        -   a —C(O)—[R⁴]_(e)—R⁵— group wherein            -   e is 0 and R⁵ is selected from the group consisting of a                divalent substituted or unsubstituted C₁-C₄ alkyl group,                C₄-C₈ cycloalkyl group, phenyl group or 5- or 6-membered                heterocyclyl group, or            -   e is 1, R⁴ is a divalent substituted or unsubstituted                C₁-C₄ alkyl group, and R⁵ is a divalent substituted or                unsubstituted C₄-C₈ cycloalkyl cycloalkyl group, phenyl                group or 5- or 6-membered heterocyclyl group,        -   a —R¹—R²— group, wherein R¹ is a divalent substituted or            unsubstituted C₁-C₄ alkyl group and R² is a divalent            substituted or unsubstituted C₄-C₈ cycloalkyl group, phenyl            group or 5- or 6-membered heterocyclyl group,        -   a —C(O)—NH— group,        -   a —(CH₂)₁₋₃—C(O)—NH—(CH₂)₁₋₃— group,        -   a —C(O)—NH—R⁴— group, wherein R⁴ is selected from a divalent            substituted or unsubstituted C₁₋₇ alkyl group, cyclohexyl            group or cyclopentyl group,        -   a —C(O)—N(R³)—R⁴— group, wherein R³ and R⁴ and the N-atom            together form a pyrrolidine ring or a piperidine ring,    -   the moiety E is selected from the group consiting of:        -   COOH,        -   a carbocylic ester group,        -   a carboxamide group,        -   a —S(O)₂—OH group,        -   a —S(O)₂—NHR⁶ group, wherein R⁶ is selected from hydrogen, a            C₁-C₆ alkyl group, a cycloalkyl group, a substituted or            unsubstituted aryl group, a substituted or unsubstituted            heterocyclyl group, or a carboxylic acid ester group,    -   the moiety A is a substituted or unsubstituted cycloalkyl, a        substituted or unsubstituted aryl, or a substituted or        unsubstituted heterocyclyl group, and is preferably selected        from the group consiting of a substituted or unsubstituted        phenyl, a substituted or unsubstituted pyridine, a substituted        or unsubstituted cyclohexyl, a substituted or unsubstituted        isoxazole, a substituted or unsubstituted oxadiazole, or a        substituted or unsubstituted pyrazole,        or pharmaceutically acceptable salts, prodrugs, stereoisomers,        crystalline forms, or polymorphs thereof.

Preferred are the compounds in the ALPHA, ALPHA′, BETA, BETA′, GAMMA,GAMMA′, DELTA, DELTA′, EPSILON, EPSILON′, THETA, THETA′, KAPPA, KAPPA′,ZETA, ZETA′, SIGMA and SIGMA′ groups wherein;

E′ is —C(O)OH, —CH₂—C(O)OH, —C₂H₄—C(O)OH—CH₂-heterocyclyl.

Preferred are the compounds in the ALPHA, ALPHA′, BETA, BETA′, GAMMA,GAMMA′, DELTA, DELTA′, EPSILON, EPSILON′, THETA, THETA′, KAPPA, KAPPA′,ZETA, ZETA′, SIGMA and SIGMA′ groups wherein;

-   -   A is selected from a substituted or unsubstituted phenyl, a        substituted or unsubstituted pyridine, a substituted or        unsubstituted cyclohexyl, a substituted or unsubstituted        isoxazol, or a substituted or unsubstituted pyrazol.

Preferred are the compounds in the ALPHA, ALPHA′, BETA, BETA′, GAMMA,GAMMA′, DELTA, DELTA′, EPSILON, EPSILON′, THETA, THETA′, KAPPA, KAPPA′,ZETA, ZETA′, SIGMA and SIGMA′ groups wherein;

-   -   A is selected from a substituted or unsubstituted phenyl, a        substituted or unsubstituted pyridine, a substituted or        unsubstituted cyclohexyl, a substituted or unsubstituted        isoxazole, a substituted or unsubstituted oxadiazole, or a        substituted or unsubstituted pyrazole, and    -   E′ is —C(O)OH, —CH₂—C(O)OH, —CH₂-heterocyclyl.

When E′ is —CH₂-heterocyclyl, it is preferably selected from

The present invention also covers pharmaceutically acceptable salts,prodrugs, stereoisomers, crystalline forms, or polymorphs of theehereinabove described compounds in the ALPHA, ALPHA′, BETA, BETA′,GAMMA, GAMMA′, DELTA, DELTA′, EPSILON, EPSILON′, THETA, THETA′, KAPPA,KAPPA′, ZETA, ZETA′, SIGMA and SIGMA′ groups.

The present invention also provides a pharmaceutical compositioncomprising the compound as defined above and a pharmaceuticallyacceptable carrier or excipient.

According to a further aspect, the present invention provides use of acompound having the following chemical structure

A-L1-B—C-D-L2-E

wherein

-   -   A is a substituted or unsubstituted alkyl, cycloalkyl, aryl, or        heterocyclyl group,    -   L1 is selected from the group consisting of:        -   an amine group —NH—        -   a substituted amine group of the formula —N(CH₃)—, —CH₂—NH—            or —CH₂—CH₂—NH—,        -   an amide group —C(O)—NH—,        -   a sulphonamide group —S(O)₂—NH—, or        -   a urea group —NHC(O)—NH—,    -   B is a substituted or unsubstituted, monocyclic, 5- or        6-membered divalent heteroaryl group,    -   C-D is selected from the following cyclic structures:        -   C-D together is a substituted or unsubstituted divalent            biphenyl group,        -   C is a substituted or unsubstituted divalent phenyl group            and D is a single bond,        -   C is a substituted or unsubstituted divalent phenyl group,            and D is a substituted or unsubstituted divalent            non-aromatic monocyclic ring which is selected from a            saturated or unsaturated divalent cycloalkyl group or a            saturated or unsaturated divalent heterocycloalkyl group,        -   C-D together is a Spiro residue, wherein            -   the first cyclic component is a benzo-fused cyclic                component wherein the ring which is fused to the phenyl                part is a 5- or 6-membered ring, optionally comprising                one or more heteroatoms; the first cyclic component                being attached to the moiety B via its phenyl part, and            -   the second cyclic component is a cycloalkyl or                cycloalkylidenyl residue which is attached to L2,    -   L2 is selected from the group consisting of:        -   a single bond,        -   a divalent residue having the following structure:

—[R¹]_(a)—[R²]_(b)—[C(O)]_(c)—[N(R³)]_(d)—[R⁴]_(e)—[R⁵]_(f)—

-   -   -   wherein        -   a is 0 or 1,        -   b is 0 or 1,        -   c is 0 or 1,        -   d is 0 or 1,        -   e is 0 or 1,        -   f is 0 or 1,        -   with the proviso that (a+b+c+d+e+f)>0, and c=1 if d=1,        -   R¹, R², R⁴ and R⁵, which can be the same or different, are a            substituted or unsubstituted divalent alkyl, cycloalkyl,            alkenyl, alkynyl, alkylene, aryl or heterocyclyl residue,        -   R³ is H or hydrocarbyl, or R³ and R⁴ form together with the            nitrogen atom to which they are attached a 5- or 6-membered            heterocycloalkyl group,        -   an alkylidenyl group which is linked to the moiety D via a            double bond, and        -   E is selected from the group consisting of:        -   a sulphonic acid group and derivatives thereof,        -   a carboxyl group and derivatives thereof, wherein the            carboxyl carbon atom is attached to L2,        -   a phosphonic acid group and derivatives thereof,        -   an alpha-keto hydroxyalkyl group,        -   a hydroxyalkyl group wherein the carbon atom bonded to the            hydroxyl group is further substituted with one or two            trifluoro-methyl groups,        -   a substituted or unsubstituted five-membered heterocyclyl            residue having in the ring at least two heteroatoms and at            least one carbon atom, wherein            -   the at least one carbon atom of the ring is bonded to                two heteroatoms;            -   at least one of the heteroatoms to which the carbon atom                of the ring is bonded is a member of the ring;            -   and at least one of the heteroatoms to which the carbon                atom of the ring is bonded or at least one of the                heteroatoms of the ring is bearing a hydrogen atom;

    -   or a prodrug or a pharmaceutically acceptable salt thereof for        the manufacture of a medicament for the treatment of DGAT1        associated disorders.

According to a further aspect, the present invention provides use of acompound having the following chemical structure

A-L1-B—C-D-L2-E

-   -   wherein    -   A is a substituted or unsubstituted alkyl, cycloalkyl, aryl, or        heterocyclyl group,    -   L1 is selected from the group consisting of:        -   an amine group —NH—        -   a substituted amine group of the formula —N(CH₃)—, —CH₂—NH—            or —CH₂—CH₂—NH—,        -   an amide group —C(O)—NH—,        -   a sulphonamide group —S(O)₂—NH—, or        -   a urea group —NHC(O)—NH—,    -   B is a substituted or unsubstituted, monocyclic, 5- or        6-membered divalent heteroaryl group,    -   C-D is selected from the following cyclic structures:        -   C-D together is a substituted or unsubstituted divalent            biphenyl group,        -   C is a substituted or unsubstituted divalent phenyl group            and D is a single bond,        -   C is a substituted or unsubstituted divalent phenyl group,            and D is a substituted or unsubstituted divalent            non-aromatic monocyclic ring which is selected from a            saturated or unsaturated divalent cycloalkyl group or a            saturated or unsaturated divalent heterocycloalkyl group,        -   C-D together is a spiro residue, wherein            -   the first cyclic component is a benzo-fused cyclic                component wherein the ring which is fused to the phenyl                part is a 5- or 6-membered ring, optionally comprising                one or more heteroatoms, the first cyclic component                being attached to the moiety B via its phenyl part, and            -   the second cyclic component is a cycloalkyl or                cycloalkylidenyl residue which is attached to L2,    -   L2 is selected from the group consisting of:        -   a single bond,        -   a divalent residue having the following structure:

—[R¹]_(a)—[R²]_(b)—[C(O)]_(c)—[N(R³)]_(d)—[R⁴]_(e)—[R⁵]_(f)—

-   -   -   wherein        -   a is 0 or 1,        -   b is 0 or 1,        -   c is 0 or 1,        -   d is 0 or 1,        -   e is 0 or 1,        -   f is 0 or 1,        -   with the proviso that (a+b+c+d+e+f)>0, and c=1 if d=1,        -   R¹, R², R⁴ and R⁵, which can be the same or different, are a            substituted or unsubstituted divalent alkyl,.cycloalkyl,            alkenyl, alkynyl, alkylene, aryl or heterocyclyl residue,        -   R³ is H or hydrocarbyl, or R³ and R⁴ form together with the            nitrogen atom to which they are attached a 5- or 6-membered            heterocycloalkyl group,        -   an alkylidenyl group which is linked to the moiety D via a            double bond,            with the proviso that L2 is not —C(O)—[R⁴]_(e)—[R⁵]_(f)—            when C is a substituted or unsubstituted divalent phenyl            group and D is a single bond,

    -   E is selected from the group consisting of:        -   a sulphonic acid group and derivatives thereof,        -   a carboxyl group and derivatives thereof, wherein the            carboxyl carbon atom is attached to L2,        -   a phosphonic acid group and derivatives thereof,        -   an alpha-keto hydroxyalkyl group,        -   a hydroxyalkyl group wherein the carbon atom bonded to the            hydroxyl group is further substituted with one or two            trifluoro-methyl groups,        -   a substituted or unsubstituted five-membered heterocyclyl            residue having in the ring at least two heteroatoms and at            least one carbon atom, wherein            -   the at least one carbon atom of the ring is bonded to                two heteroatoms;            -   at least one of the heteroatoms to which the carbon atom                of the ring is bonded is a member of the ring;            -   and at least one of the heteroatoms to which the carbon                atom of the ring is bonded or at least one of the                heteroatoms of the ring is bearing a hydrogen atom;

    -   or a prodrug or a pharmaceutically acceptable salt thereof for        the manufacture of a medicament for the treatment of DGAT1        associated disorders.

In a preferred embodiment, the compound used for the manufacture of themedicament is one of those as defined in claims 1 to 24, or is one ofthose as defined in the ALPHA, ALPHA′, BETA, BETA′, GAMMA, GAMMA′,DELTA, DELTA′, EPSILON, EPSILON′, THETA, THETA′, KAPPA, KAPPA′, ZETA,ZETA′ groups.

Among the preferred DGAT1 associated disorders, the following can bementioned:

Metabolic disorders such as obesity, diabetes, anorexia nervosa,bulimia, cachexia, syndrome X, insulin resistance, hypoglycemia,hyperglycemia, hyperuricemia, hyperinsulinemia, hypercholesterolemia,hyperlipidemia, dyslipidemia, mixed dyslipidemia, hypertriglyceridemia,pancreatitis, and nonalcoholic fatty liver disease; cardiovasculardiseases, such as atherosclerosis, arteriosclerosis, acute heartfailure, congestive heart failure, coronary artery disease,cardiomyopathy, myocardial infarction, angina pectoris, hypertension,hypotension, stroke, ischemia, ischemic reperfusion injury, aneurysm,restenosis, and vascular stenosis; neoplastic diseases, such as solidtumors, skin cancer, melanoma, lymphoma, and endothelial cancers, forexample, breast cancer, lung cancer, colorectal cancer, stomach cancer,other cancers of the gastrointestinal tract (for example, esophagealcancer and pancreatic cancer), prostate cancer, kidney cancer, livercancer, bladder cancer, cervical cancer, uterine cancer, testicularcancer, and ovarian cancer; dermatological conditions, such as acnevulgaris.

Preferably, the DGAT1 associated disorder is impaired glucose tolerance,Type 2 diabetes and obesity.

In yet another aspect, the present invention provides methods of usingthe compound or composition of the invention as an anorectic.

The compounds of the invention depending on the nature of thesubstituents possess one or more stereogenic centers. The resultingdiastereoisomers, optical isomers, i.e., enantiomers, and geometricisomers, and mixtures thereof, are encompassed by the instant invention.

In a preferred embodiment, the moiety A is a substituted orunsubstituted phenyl group or a 6-membered heteroaryl group comprisingone or two nitrogen atoms in the ring, L1 is —NH—, the moiety B is asubstituted or unsubstituted divalent pyrimidine residue, the moiety C-Dis selected from a substituted or unsubstituted divalent phenyl group(i.e. C) in combination with a single bond (i.e. D) or from asubstituted or unsubstituted divalent phenyl group (i.e. C) incombination with a 5- or 6-membered cycloalkyl group (i.e. D), L2 isselected from a divalent C₁-C₄ alkyl group or from a divalent—C(O)—C₁-C₄ alkyl group, and E is selected from a carboxyl group or aderivative thereof.

In another preferred embodiment, the moiety A is a substituted orunsubstituted phenyl group, L1 is —NH—, the moiety B is a substituted orunsubstituted divalent oxazole residue, the moiety C-D is selected froma substituted or unsubstituted divalent phenyl group (i.e. C) incombination with a 5- or 6-membered cycloalkyl group (i.e. D), asubstituted or unsubstituted divalent biphenyl group (i.e. C=D=phenyl),a substituted or unsubstituted divalent phenyl group (i.e. C) incombination with a divalent 5- or 6-membered non-aromatic heterocyclylgroup, preferably a tetrahydro-pyridine group (i.e. D), L2 is selectedfrom a divalent C₁-C₄ alkyl group, a divalent C₁-C₄alkyl-C(O)—N(R)—C₁-C₄ alkyl group wherein R is H or a C₁-C₄ alkyl group,a divalent —C(O)—C₁-C₄ alkyl group, a divalent —C(O)—C₅-C₆ cycloalkylgroup, a divalent —C(O)-phenyl group, a —C(O)— group, or a divalent—R¹—R²— group wherein R¹ is cyclohexyl and R² is C₁-C₄ alkyl, and E isselected from a carboxyl group or derivative thereof or a sulphonic acidor derivative thereof, preferably a sulphonamide group.

In another preferred embodiment, the moiety A is a substituted orunsubstituted phenyl group, L1 is —NH—, the moiety B is a substituted orunsubstituted divalent thiazole residue, the moiety C-D is selected froma substituted or unsubstituted divalent phenyl group (i.e. C) incombination with a 5- or 6-membered cycloalkyl group (i.e. D) or from asubstituted or unsubstituted biphenyl group (i.e. C=D=phenyl), L2 isselected from a divalent C₁-C₄ alkyl group or from a divalent—C(O)—C₁-C₄ alkyl group, and E is selected from a carboxyl group or aderivative thereof.

In another preferred embodiment, the moiety A is selected fromsubstituted or unsubstituted alkyl, cycloalkyl, phenyl or a 5- or6-membered heterocyclyl group comprising one or two nitrogen atoms inthe ring, preferably pyridine, pyrazole or isoxazole, L1 is selectedfrom —N(H)—, —C(O)NH—, or —NHC(O)—, the moiety B is a substituted orunsubstituted divalent pyridine, the moiety C-D is a divalentsubstituted or unsubstituted phenyl (i.e. C) in combination with a 5- or6-membered cycloalkyl (i.e. D), L2 is a C₁-C₄ alkyl group or a spiroresidue, and E is a carboxyl group or a derivative thereof. Preferably,the amino group representing L1 is attached to the pyridine residuerepresenting moiety B either via ring position 2 or ring position 3.

In another preferred embodiment, the moiety A is selected from asubstituted or unsubstituted alkyl, cycloalkyl, phenyl or a 5- or6-membered heterocyclyl group comprising one or two nitrogen atoms inthe ring, preferably pyridine, L1 is selected from —N(H)—, —C(O)NH—, or—NHC(O)—, the moiety B is a divalent substituted or unsubstitutedpyridazine group, the moiety C-D is selected from a substituted orunsubstituted divalent phenyl group (i.e. C) in combination with asingle bond (i.e. D), from a substituted or unsubstituted divalentphenyl group (i.e. C) in combination with a 5- or 6-membered cycloalkylgroup which is optionally comprising a heteroatom like nitrogen (i.e.D), L2 is selected from a C₁-C₄ alkyl group, a —C(O)—N(R¹)—R²— groupwherein R¹ and R² are joined so as to form a 5- or 6-memberednon-aromatic heterocyclyl group, a —C(O)—N(R¹)—R²— group wherein R¹ is aC₁-C₄ alkyl group and R² is a 5- or 6-membered cycloalkyl group or aC₁-C₄ alkyl group, and E is selected from a carboxyl group or derivativethereof or a substituted or unsubstituted five-membered heterocyclylresidue having at least two heteroatoms and at least one carbon atom inthe ring, preferably a tetrazole residue or an oxo-substitutedoxadiazole residue.

Particular embodiments of the invention are the compounds:

(4-{4-[2-(3-Fluorophenylamino)-pyrimidin-5-yl]-phenyl}-cyclohexyl)-aceticacid,

{4-[4-(2-Phenylaminopyrimidin-5-yl)-phenyl]-cyclohexyl}-acetic acid,

4-{4-[2-(3-Fluorophenylamino)-pyrimidin-5-yl]-phenyl}-2,2-dimethyl-4-oxo-butyricacid,

(1S,2S)-2-{4-[2-(3-Fluorophenylamino)-pyrimidin-5-yl]-benzoyl}-cyclopentanecarboxylicacid,

(1S,2S)-2-{4-[2-(3-Chlorophenylamino)-pyrimidin-5-yl]-benzoyl}-cyclopentanecarboxylicacid,

(4-{4-[2-(3-Methoxyphenylamino)-thiazol-4-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[2-(3-Fluorophenylamino)-thiazol-4-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[2-(2-Chlorophenylamino)-thiazol-4-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[2-(3-Cyanophenylamino)-thiazol-4-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[2-(3-Trifluoromethylphenylamino)-thiazol-4-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[2-(3-Fluorophenylamino)-thiazol-4-yl]-phenyl}-cyclohexyl)-aceticacid,

3-{4-[2-(3-Fluorophenylamino)-thiazol-4-yl]-biphenyl-4-yl}-propionicacid,

{4-[2-(3-Fluorophenylamino)-thiazol-4-yl]-biphenyl-4-yl}-acetic acid,

(4-{4-[2-(3-Chlorophenylamino)-oxazol-5-yl]-phenyl}-cyclohexylyaceticacid,

(4-{4-[2-(4-Chlorophenylamino)-oxazol-5-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[2-(4-Methoxyphenylamino)-oxazol-5-yl]-phenyl}-cyclohexylyaceticacid,

(4-{4-[2-(2-Fluorophenylamino)-oxazol-5-yl]-phenyl}-cyclohexylyaceticacid,

{4-[4-(2-Phenylaminooxazol-5-yl)-phenyl]-cyclohexyl}-acetic acid,

(4-{4-[2-(3-Fluorophenylamino)-oxazol-5-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[2-(2-Chlorophenylamino)-oxazol-5-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[2-(3-Cyanophenylamino)-oxazol-5-yl]-phenyl}-cyclohexyl)-aceticacid,

{4-[4-(2-Cyclohexylaminooxazol-5-yl)-phenyl]-cyclohexyl}-acetic acid,

(4-[2-(3,4-Dichlorophenylamino)-oxazol-5-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-(2-(3-Chloro-4-fluorophenylamino)-oxazol-5-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-[2-(4-Chloro-3-trifluoromethylphenylamino)-oxazol-5-yl]-phenyl}-cyclohexylyaceticacid,

(4-{4-[2-(3,5-Difluorophenylamino)-oxazol-5-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[2-(3,5-Dichlorophenylamino)-oxazol-5-yl]-phenyl}-cyclohexylyaceticacid,

(4-{4-[2-(2-Chloro-4-trifluoromethylphenylamino)-oxazol-5-yl]-phenyl}-cyclohexylyaceticacid,

(4-{4′-[2-(2-Trifluoromethylphenylamino)-oxazol-5-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[2-(3-Fluoro-4-methylphenylamino)-oxazol-5-yl]-phenyl}-cyclohexyl)-aceticacid,

{4-[4-(2-p-Tolylaminooxazol-5-yl)-phenyl]-cyclohexyl}-acetic acid,(4-{4-[2-(3-Chloro-4-methylphenylamino)-oxazol-5-yl]-phenylycyclohexyl}-aceticacid,

4-(4-{4-[2-(3-Chlorophenylamino)-oxazol-5-yl]-phenyl}-cyclohexyl)-butyricacid,

(E)-4-(4-{4-[2-(3-Chlorophenylamino)-oxazol-5-yl]-phenyl}-cyclohexyl)-but-2-enoicacid,

3-[2-(4-{4-[2-(3-Chlorophenylamino)-oxazol-5-yl]-phenyl}-cyclohexyl)-acetylamino]-propionicacid,

{[2-(4-{4-[2-(3-Chlorophenylamino)-oxazol-5-yl]-phenyl}-cyclohexyl)-acetyl]-methyl-amino}-aceticacid,

{4′-[2-(3-Chlorophenylamino)-oxazol-5-yl]-biphenyl-4-yl}-acetic acid,

3-{4′-[2-(3-Chlorophenylamino)-oxazol-5-yl]-biphenyl-4-yl}-propionicacid,

4-{4′-[2-(3-Chlorophenylamino)-oxazol-5-yl]-biphenyl-4-yl}-2,2-dimethyl-4-oxo-butyricacid,

4-{4′-[2-(3-Chlorophenylamino)-oxazol-5-yl]-biphenyl-4-yl}-4-oxo-butyricacid,

4-{4′-[2-(3-Chlorophenylamino)-oxazol-5-yl]-biphenyl-4-carbonyl}-cyclohexanecarboxylicacid,

(4-{4-[2-(3-Chlorophenylamino)-oxazol-5-yl]-phenyl}-3,6-dihydro-2H-pyridin-1-yl)-oxo-aceticacid,

4-{4-[2-(3-Chloro-phenylamino)-oxazol-5-yl]-phenyl}-3,6-dihydro-2H-pyridine-1-sulfonicacid amide,

4-{4-[2-(3-Chloro-phenylamino)-oxazol-5-yl]-phenyl}-3,6-dihydro-2H-pyridine-1-sulfonicacid amide-N-carboxylic acid tert-butyl ester,

4-(4-{4-[2-(3-Chloro-phenylamino)-oxazol-5-yl]-phenyl}-3,6-dihydro-2H-pyridin-1-yl)-2,2-dimethyl-4-oxo-butyricacid,

4-(4-{4-[2-(3-Chloro-phenylamino)-oxazol-5-yl]-phenyl}-3,6-dihydro-2H-pyridin-1-yl)-4-oxo-butyricacid,

2-(4-{4-[2-(3-Chloro-phenylamino)-oxazol-5-yl]-phenyl}-3,6-dihydro-2H-pyridine-1-carbonyl)-benzoicacid,

(1R,2R)-2-(4′-[2-(3-Chlorophenylamino)-oxazol-5-yl]-biphenyl-4-carbonyl}-cyclohexanecarboxylicacid,

(trans)-2-{4′-[2-(3-Chlorophenylamino)-oxazol-5-yl]-biphenyl-4-carbonyl}-cyclohexanecarboxylicacid,

(trans)-2-{4′-[2-(3-Chlorophenylamino)-oxazol-5-yl]-biphenyl-4-carbonyl}-cyclopentanecarboxylicacid,

(4-{4′-[2-(3-Chloro-phenylamino)-oxazol-5-yl]-biphenyl-4-yl}-cyclohexyl}-aceticacid,

(4-{5-[6-(6-Trifluoromethyl-pyridin-3-ylamino)-pyridin-3-yl]-spirocyclohexylidenyl-1,1′-indanyl}-aceticacid,

(4-{5-[6-(6-Trifluoromethyl-pyridin-3-ylamino)-pyridin-3-yl]-spirocyclohexyl-1,1′-indanyl}-aceticacid,

(4-{4-[6-(3-Chloro-phenylamino)-pyridin-3-yl]-phenylycyclohexyl}-aceticacid,

(4-{4-[6-(3-methylphenylamino)-pyridin-3-yl]-phenylycyclohexyl}-aceticacid,

(4-{4-[6-(3-Trifluoromethylphenylamino)-pyridin-3-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-6-(3-Methoxyphenylamino)-pyridin-3-yl]-phenyl}-cyclohexylyaceticacid,

(4-{4-[6-(2-Fluorophenylamino)-pyridin-3-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[6-(2-Methoxyphenylamino)-pyridin-3-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[6-(2-Methoxyphenylamino)-pyridin-3-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[5-(6-Trifluoromethyl-pyridin-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[5-(Pyridin-2-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-(5-Phenylaminopyridin-2-yl)-phenyl]-cyclohexyl}-acetic acid,

(4-{4-[5-(5-Cyanopyridin-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[5-(5-Trifluoromethylpyridin-2-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[5-(4-Trifluoromethylphenylamino)-pyridin-2-yl]-phenylycyclohexyl}-aceticacid,

(4-{4-[5-(5-Methylpyridin-2-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[5-(5-Trifluoromethylpyridin-2-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid methyl ester,

(4-{4-[5-(5-Chloropyridin-2-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[5-(6-Methoxypyridin-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexylyaceticacid,

(4-{4-[5-(5-Fluoropyridin-2-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[5-(6-Acetylaminopyridin-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,

{4-[4-(3-Methoxy-5-phenylamino-pyridin-2-yl)-phenyl]-cyclohexyl}-aceticacid,

{4-[4-(3-Methoxy-5-(3-fluorophenyl)amino-pyridin-2-yl]-phenyl}-cyclohexylyaceticacid,

{4-[4-(3-Methoxy-5-(4-trifluoromethyl-phenyl)amino-pyridin-2-yl)-phenyl]-cyclohexyl}-aceticacid,

{4-[4-(3-Methoxy-5-(3-chlorophenyl)amino-pyridin-2-yl)-phenyl]-cyclohexyl}-aceticacid,

(4-{4-[5-(3-Fluoro-phenylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[5-(3-Chloro-phenylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[5-(1-Methyl-1H-pyrazol-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[5-(5-Fluoro-6-methoxy-pyridin-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexylyaceticacid,

(4-{4-[5-(Isoxazol-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{5-[5-(6-Trifluoromethyl-pyridin-3-ylamino)-pyridin-2-yl]-spirocyclohexylidenyl-1,1′-indanyl}-aceticacid,

(4-{4-[6-(3-Chloro-phenylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[6-(3-Fluoro-phenylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-aceticacid,

{4-[4-(6-m-Tolylamino-pyridazin-3-yl)-phenyl]-cyclohexyl}-acetic acid,

(4-{4-[6-(3-Trifluoromethyl-phenylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[6-(3-Methoxy-phenylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[6-(3-Cyano-phenylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[6-(2-Fluoro-phenylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[6-(4-Chloro-phenylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-aceticacid,

{4-[4-(6-p-Tolylamino-pyridazin-3-yl)-phenyl]-cyclohexyl}-acetic acid,

(4-{4-[6-(4-Trifluoromethyl-phenylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[6-(3-Chloro-4-methoxy-phenylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[6-(3-Chloro-2-methyl-phenylamino)-pyridazin-3-yl]-phenyl}-cyclohexylyaceticacid,

{4-[4-(6-Phenylamino-pyridazin-3-yl)-phenyl]-cyclohexyl}-acetic acid;

(4-{4-[6-(3-Chloro-2-methoxy-phenylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[6-(2-Methoxy-phenylamino)-pyridazin-3-yl]-phenyl}-cyclohexylyaceticacid,

(4-{4-[6-(4-Methoxy-phenylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[6-(6-Trifluoromethyl-pyridin-3-ylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[6-(4-Trifluoromethoxy-phenylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[6-(4-Fluoro-phenylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[6-(6-Amino-pyridin-3-ylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-(4-[6-(Methyl-m-tolyl-amino)-pyridazin-3-yl]-phenyl}-cyclohexylyaceticacid,

[4-(4-{6-[(3-Chloro-phenyl)-methyl-amino]-pyridazin-3-yl}-phenyl)-cyclohexyl]-aceticacid,

[4-(4-{6-[(3-Methoxy-phenyl)-methyl-amino]-pyridazin-3-yl}-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[6-(2-Methyl-6-trifluoromethyl-pyridin-3-ylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[6-(3-Chloro-2-methoxy-phenylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-aceticacid,

2-{4-[6-(3-Chloro-phenylamino)-pyridazin-3-yl]-benzoylamino}-3-methyl-butyricacid,

(S)-1-{4-[6-(3-Chloro-phenylamino)-pyridazin-3-yl]-benzoyl}-pyrrolidine-2-carboxylicacid,

(1S,2R)-2-{4-[6-(3-Chloro-phenylamino)-pyridazin-3-yl]-benzoylamino}-cyclopentanecarboxylicacid,

3-{4-[6-(3-Chloro-phenylamino)-pyridazin-3-yl]-benzoylamino}-propionicacid,

(S)-3-{4-[6-(3-Chloro-phenylamino)-pyridazin-3-yl]-benzoylamino}-5-methyl-hexanoicacid,

(1S,2R)-2-{4-[6-(3-Chloro-phenylamino)-pyridazin-3-yl]-benzoylamino}-cyclohexanecarboxylicacid,

(8)-1-{4-[6-(3-Chloro-phenylamino)-pyridazin-3-yl]-benzoyl}-piperidine-2-carboxylicacid,

2-{4-[6-(3-Chloro-phenylamino)-pyridazin-3-yl]-benzoylamino}-2-methyl-propionicacid,

4-{4-[6-(3-Trifluoromethyl-phenylamino)-pyridazin-3-yl]-phenyl}-cyclohexanecarboxylicacid,

2-(4-{4-[6-(3-Chloro-phenylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-acetamide,

(6-{4-[4(2H-Tetrazol-5-ylmethyl)-cyclohexyl]-phenyl}-pyridazin-3-yl)-(6-trifluoromethyl-pyridin-3-yl)-amine,

3-(4-{4-[6-(6-Trifluoromethyl-pyridin-3-ylamino)-pyridazin-3-yl]-phenyl}-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one,

(1-{4-[6-(3-Trifluoromethyl-phenylamino)-pyridazin-3-yl]-phenyl}-piperidin-4-yl)-aceticacid,

(4-{4-[4-Methyl-6-(6-trifluoromethyl-pyridin-3-ylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[4-Methyl-6-(4-trifluoromethyl-phenylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[5-(6-Trifluoromethyl-pyridin-3-ylamino)-pyrazin-2-yl]-phenyl}-cyclohexylyaceticacid,

(4-{4-[5-(2,2-Dimethyl-propionylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[5-(Benzooxazol-2-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[6-(6-Methoxy-pyridin-3-ylamino)-5-methyl-pyridin-3-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[5-Fluoro-6-(6-methoxy-pyridin-3-ylamino)-pyridin-3-yl]-phenyl}-cyclohexyl)-aceticacid,

Oxo-(4-{4-[6-(6-trifluoromethyl-pyridin-3-ylamino)-pyridin-3-yl]-phenyl}-cyclohexyl)-aceticacid,

{4-[4-(5-Acetylamino-pyridin-2-yl)-phenyl]-cyclohexyl}-acetic acid,

(4-{4-[5-(3-Trifluoromethyl-benzoylamino)-pyridin-2-yl]-phenyl}-cyclohexylyaceticacid,

[4-(4-{5-[(Pyridine-2-carbonyl)-amino]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid,

[4-(4-{5-[3-(4-Trifluoromethoxy-phenyl)ureido]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid,

[4-(4-{5-[3-(2-Trifluoromethyl-phenyl)-ureido]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid,

(4-{4-[5-(3-o-Tolyl-ureido)-pyridin-2-yl]-phenyl}-cyclohexyl]-aceticacid,

[4-(4-{5-[(1-Methyl-1H-indole-3-carbonyl)-amino]-pyridin-2-yl)-phenyl)-cyclohexyl]-aceticacid,

[4-(4-{5-[(1H-Indole-3-carbonyl)-amino]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid,

[4-(4-{5-[(Pyridine-3-carbonyl)-amino]-pyridin-2-yl}-phenylycyclohexyl]-aceticacid,

[4-(4-{5-[(6-Methyl-pyridine-3-carbonyl)-amino]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid,

[4-(4-{5-[(5-Bromo-pyridine-3-carbonyl)-amino]-pyridin-2-yl}-phenylycyclohexyl]-aceticacid,

[4-(4-{5-[(5-Chloro-6-methoxy-pyridine-3-carbonyl)-amino]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid,

[4-(4-{5-[(5-Isobutyl-isoxazole-3-carbonyl)-amino]-pyridin-2-yl}-phenylycyclohexyl]-aceticacid,

[4-(4-{5-[(3-tert-Butyl-1-methyl-1H-pyrazole-4-carbonyl)-amino]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid,

[4-(4-{5-[(5-tert-Butyl-1H-pyrazole-3-carbonyl)-amino]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid,

[4-(4-{5-[(5-Isopropyl-isoxazole-3-carbonyl)-amino]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid,

{4-[4-(5-Isobutoxycarbonylamino-pyridin-2-yl)-phenyl]-cyclohexyl}-aceticacid,

[4-(4-{5-[((S)-5-Oxo-pyrrolidine-2-carbonyl)-amino]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid,

(4-{4-[5-(4-Fluoro-3-trifluoromethyl-benzoylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[5-(4-Trifluoromethyl-benzoylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,

[4-(4-{5-[(6-Trifluoromethyl-pyridine-3-carbonyl)-amino]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid,

(4-{4-[5-(3-Fluoro-5-trifluoromethyl-benzoylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,

[4-(4-{5-[(Tetrahydro-pyran-4-carbonyl)-amino]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid,

[4-(4-{5-[(5-Bromo-2-methoxy-pyridine-3-carbonyl)-amino]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid,

[4-(4-[5-[(1,5-Dimethyl-1H-pyrazole-3-carbonyl)-amino]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid,

[4-(4-{5-[(5-Methoxy-1H-indole-3-carbonyl)-amino]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid,

[4-(4-{5-[(2,5-Dimethyl-1H-pyrrole-3-carbonyl)-amino]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid,

[4-(4-{5-[(1-Methyl-5-trifluoromethyl-1H-pyrazole-4-carbonyl)-amino]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid,

{4-[4-(5-{[4-(Morpholine-4-sulfonyl)-1H-pyrrole-2-carbonyl]-amino}-pyridin-2-yl)-phenyl]-cyclohexyl}-aceticacid,

(4-{4-[5-(2-Fluoro-2-methyl-propionylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,

[4-(4-{5-[(1-Methyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl)-amino]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid methyl ester,

(4-{4-[5-(2-Methyl-2-pyrazol-1-yl-propionylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,

[4-(4-{5-[(5-isopropyl-isoxazole-4-carbonyl)-amino]-pyridin-2-yl)-phenyl}-cyclohexyl]-aceticacid,

[4-(4-{5-[(1-Methyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl)-amino]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid,

[4-(4-{5-[(5-Cyclopropyl-isoxazole-4-carbonyl)-amino]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid,

[4-(4-{5-[(5-Cyclopropyl-isoxazole-4-carbonyl)amino]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid methyl ester,

[4-(4-{5-[(5-Cyclopropyl-isoxazole-3-carbonyl)-amino]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid,

[4-(4-{5-[(6-Methoxy-pyridine-3-carbonyl)-amino]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid,

(4-{4-[5-(2,2-Dimethyl-butyrylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[5-(2-Methoxy-2-methyl-propionylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,

[4-(4-{5-[(1,5-Dimethyl-1H-pyrazole-4-carbonyl)-amino]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid,

(4-{4-[5-(Tetrahydro-pyran-4-yloxycarbonylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,

{4-[4-(5-Cyclopropylmethoxycarbonylamino-pyridin-2-yl)-phenyl]-cyclohexyl}-aceticacid,

(4-{4-[5-(Tetrahydro-furan-2-ylmethoxycarbonylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[5-(Tetrahydro-pyran-2-ylmethoxycarbonylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[5-(3-Methyl-oxetan-3-ylmethoxycarbonylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[5-(Tetrahydro-pyran-4-ylmethoxycarbonylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[5-(2-Methyl-pyridin-3-ylmethoxycarbonylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,

[4-(4-{5-[3-(4-Chloro-3-trifluoromethyl-phenyl)-ureido]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid,

{4-[4-(5-Isopropylcarbamoyl-pyridin-2-yl)-phenyl]-cyclohexyl}-aceticacid,

{4-[4-(6-Carbamoyl-pyridin-2-yl)-phenyl]-cyclohexyl}-acetic acid,

{4-[4-(6-Isopropylcarbamoyl-pyridin-2-yl)-phenyl]-cyclohexyl}-aceticacid,

(4-{4-[5-(6-Trifluoromethyl-pyridin-3-ylcarbamoyl)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[5-(4-Trifluoromethyl-benzenesulfonylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[5-(3-Trifluoromethyl-benzenesulfonylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[5-(1,2-Dimethyl-1H-imidazole-4-sulfonylamino)-pyridin-2-yl]-phenyl}cyclohexyl)-aceticacid,

(4-{4-[5-(5-Fluoro-pyridin-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[5-(6-Isopropoxy-pyridin-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[5-(5-Bromo-pyridin-2-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[5-(2-Methoxy-pyrimidin-5-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[5-(6-Methylsulfanyl-pyridin-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[5-([1,2,4]Triazin-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[5-(2-Dimethylamino-pyrimidin-5-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[5-(5-Methylsulfanyl-pyridin-2-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[5-(3,5-Difluoro-pyridin-2-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[5-(6-Trifluoromethyl-pyridin-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid methyl ester,

(4-{4-[5-(5-Chloro-6-methoxy-pyridin-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[5-(5-Fluoro-4-methyl-pyridin-2-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[5-(3-Chloro-5-methyl-pyridin-2-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[5-(5-Difluoromethyl-6-methoxy-pyridin-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[5-(5-Methanesulfonyl-pyridin-2-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[3-Fluoro-5-(6-trifluoromethyl-pyridin-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[5-(1H-Benzoimidazol-2-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[5-(5-Trifluoromethyl-(1,3,4]oxadiazol-2-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[5-(6-Methyl-benzooxazol-2-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[5-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[5-(6-Chloro-benzooxazol-2-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid methyl ester,

(4-{4-[5-(6-Chloro-benzooxazol-2-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[5-(5-Chloro-6-methoxy-benzooxazol-2-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[5-(5-tert-Butyl-[1,3,4]oxadiazol-2-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[2-(6-Trifluoromethyl-pyridin-3-ylamino)-pyrimidin-5-yl[-phenyl}-cyclohexyl)-aceticacid,

(4-{4-[2-(5-Chloro-pyridin-2-ylamino)-pyrimidin-5-yl]-phenyl}-cyclohexyl)-aceticacid

Oxo-(4-{4-[6-(6-trifluoromethyl-pyridin-3-ylamino)-pyridin-3-yl]-phenyl}-piperidin-1-yl)-aceticacid,

(4-Hydroxy-4-{4-[6-(6-trifluoromethyl-pyridin-3-ylamino)-pyridin-3-yl]-phenyl}-piperidin-1-yl)-aceticacid,

(4-{4-[6-(2-Methyl-6-trifluoromethyl-pyridin-3-ylamino)-pyridin-3-yl]-phenyl}-cyclohexyl)-aceticacid,

or in any case a pharmaceutically acceptable salt thereof.

In a further embodiement, the above listed compounds are in the form oftheir corresponding potassium, sodium, hydrochloric, methanesulfonic,phosphoric or sulfuric acids salts. The salts can be prepared by theherein described methods.

In a further embodiment, the above listed compounds, wherein the moietyD is a substituted or unsubstituted divalent cyclohexyl group, are in atrans configuration as represented by figure “B”

Use of a compound as herein described, or a prodrug or apharmaceutically acceptable salt thereof for the manufacture of amedicament for the treatment of DGAT1 associated disorders.

The processes described herein for the preparation of compounds abovemay be conducted under inert atmosphere, preferably under nitrogenatmosphere.

In starting compounds and intermediates which are converted to thecompounds of the present invention in a manner described herein,functional groups present, such as amino, thiol, carboxyl and hydroxylgroups, are optionally protected by conventional protecting groups thatare common in preparative organic chemistry. Protected amino, thiol,carboxyl and hydroxyl groups are those that can be converted under mildconditions into free amino thiol, carboxyl and hydroxyl groups withoutthe molecular framework being destroyed or other undesired sidereactions taking place.

The purpose of introducing protecting groups is to protect thefunctional groups from undesired reactions with reaction componentsunder the conditions used for carrying out a desired chemicaltransformation. The need and choice of protecting groups for aparticular reaction is known to those skilled in the art and depends onthe nature of the functional group to be protected (hydroxyl group,amino group, etc.), the structure and stability of the molecule of whichthe substituent is a part and the reaction conditions.

Well-known protecting groups that meet these conditions and theirintroduction and removal are described, e.g., in McOmie, “ProtectiveGroups in Organic Chemistry”, Plenum Press, London, N.Y. (1973); andGreene and Wuts, “Protective Groups in Organic Synthesis”, John Wileyand Sons, Inc., NY (1999).

The above-mentioned reactions are carried out according to standardmethods, in the presence or absence of diluent, preferably, such as areinert to the reagents and are solvents thereof, of catalysts, condensingor said other agents, respectively and/or inert atmospheres, at lowtemperatures, RT or elevated temperatures, preferably at or near theboiling point of the solvents used, and at atmospheric orsuper-atmospheric pressure. The preferred solvents, catalysts andreaction conditions are set forth in the appended illustrative Examples.

The invention further includes any variant of the present processes, inwhich an intermediate product obtainable at any stage thereof is used asstarting material and the remaining steps are carried out, or in whichthe starting materials are formed in situ under the reaction conditions,or in which the reaction components are used in the form of their saltsor optically pure antipodes.

Compounds of the invention' and intermediates can also be converted intoeach other according to methods generally known per se.

The invention also relates to any novel starting materials,intermediates and processes for their manufacture.

Depending on the choice of starting materials and methods, the newcompounds may be in the form of one of the possible isomers or mixturesthereof, for example, as substantially pure geometric (cis or trans)isomers, diastereomers, optical isomers (antipodes), racemates ormixtures thereof. The aforesaid possible isomers or mixtures thereof arewithin the purview of this invention.

Any resulting mixtures of isomers can be separated on the basis of thephysicochemical differences of the constituents, into the pure geometricor optical isomers, diastereomers, racemates, for example, bychromatography and/or fractional crystallization.

Finally, compounds of the invention are either obtained in the freeform, or in a salt form thereof, preferably, in a pharmaceuticallyacceptable salt form thereof, or as a prodrug derivative thereof.

Compounds of the instant invention which contain acidic groups may beconverted into salts with pharmaceutically acceptable bases. Such saltsinclude alkali metal salts, like sodium, lithium and potassium salts;alkaline earth metal salts, like calcium and magnesium salts; ammoniumsalts with organic bases, e.g., trimethylamine salts, diethylaminesalts, tris(hydroxymethyl)methylamine salts, dicyclohexylamine salts andN-methyl-D-glucamine salts; salts with amino acids like arginine, lysineand the like. Salts may be formed using conventional methods,advantageously in the presence of an ethereal or alcoholic solvent, suchas a lower alkanol. From the solutions of the latter, the salts may beprecipitated with ethers, e.g., diethyl ether or acetonitrile. Resultingsalts may be converted into the free compounds by treatment with acids.These or other salts can also be used for purification of the compoundsobtained.

Alternatively, alkali metal salts of acidic compounds may also beprepared from the corresponding ester, i.e. the methyl or ethylcarboxylic acid ester. Treatment of the appropriate ester with analkaline base such as sodium, potassium or lithium hydroxide in anethereal or alcoholic solvent may directly afford the alkali metal salt,which may be precipitated from a reaction mixture by addition of aco-solvent such as diethyl ether or acetonitrile.

Compounds of the invention, in general, may be converted into acidaddition salts, especially pharmaceutically acceptable salts. These areformed, e.g., with inorganic acids, such as mineral acids, e.g.,sulfuric acid, phosphoric or hydrohalic acid, or with organic carboxylicacids, such as (C₁-C₄)-alkanecarboxylic acids which, e.g., areunsubstituted or substituted by halogen, e.g., acetic acid, such assaturated or unsaturated dicarboxylic acids, e.g., oxalic, succinic,maleic or fumaric acid, such as hydroxycarboxylic acids, e.g., glycolic,lactic, malic, tartaric or citric acid, such as amino acids, e.g.,aspartic or glutamic acid, or with organic sulfonic acids, such as(C₁-C₄)-alkylsulfonic acids, e.g., methanesulfonic acid; or arylsulfonicacids which are unsubstituted or substituted (for example by halogen).Preferred are salts formed with hydrochloric acid, maleic acid andmethanesulfonic acid.

These salts may be prepared by suspension or dissolution of thepreferred compounds in an organic solvent or water or appropriatemixture of the two, followed by addition of the appropriate acid. Theresulting salt may be isolated by precipitation and or removal ofsolvent. Precipitation of the salt may be enhanced by addition ofco-solvents such as ethereal solvents or acetonitrile, cooling, seeding,or other methods known to those skilled in the art.

Prodrug derivatives of any compound of the invention are derivatives ofsaid compounds which following administration release the parentcompound in vivo via some chemical or physiological process, e.g., aprodrug on being brought to the physiological pH or through enzymeaction is converted to the parent compound. Exemplary prodrugderivatives are, e.g., esters of free carboxylic acids and S-acyl andO-acyl derivatives of thiols, alcohols or phenols, wherein acyl has ameaning as defined herein. Preferred are pharmaceutically acceptableester derivatives convertible by solvolysis under physiologicalconditions to the parent carboxylic acid, e.g., lower alkyl esters,cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- ordi-substituted lower alkyl esters, such as the ω-(amino, mono- ordi-lower alkylamino, carboxy, lower alkoxycarbonyl)-lower alkyl esters,the α-(lower alkanoyloxy, lower alkoxycarbonyl or di-loweralkylaminocarbonyl)-lower alkyl esters, such as the pivaloyloxymethylester and the like conventionally used in the art.

In view of the close relationship between the free compounds, theprodrug derivatives and the compounds in the form of their salts,whenever a compound is referred to in this context, a prodrug derivativeand a corresponding salt is also intended, provided such is possible orappropriate under the circumstances.

The compounds, including their salts, can also be obtained in the formof their hydrates, or include other solvents used for theircrystallization.

As described herein above, the compounds of the present invention may beemployed for the treatment of conditions mediated by DGAT1 activity.Such compounds may thus be employed therapeutically for the treatment ofimpaired glucose tolerance, Type 2 diabetes and obesity.

In yet another aspect, the present invention provides methods of using acompound or composition of the invention to treat or prevent a diseaseor condition associated with DGAT1. Disease and conditions associatedwith lipid metabolism and cell proliferation, and complications thereof,may be treated with the subject compounds and compositions. In one groupof embodiments, diseases and conditions, including chronic diseases, ofhumans and other species that can be treated with inhibitors of DGAT1function include, but are not limited to, metabolic disorders such asobesity, diabetes, anorexia nervosa, bulimia, cachexia, syndrome X,insulin resistance, hypoglycemia, hyperglycemia, hyperuricemia,hyperinsulinemia, hypercholesterolemia, hyperlipidemia, dyslipidemia,mixed dyslipidemia, hypertriglyceridemia, pancreatitis, and nonalcoholicfatty liver disease; cardiovascular diseases, such as atherosclerosis,arteriosclerosis, acute heart failure, congestive heart failure,coronary artery disease, cardiomyopathy, myocardial infarction, anginapectoris, hypertension, hypotension, stroke, ischemia, ischemicreperfusion injury, aneurysm, restenosis, and vascular stenosis;neoplastic diseases, such as solid tumors, skin cancer, melanoma,lymphoma, and endothelial cancers, for example, breast cancer, lungcancer, colorectal cancer, stomach cancer, other cancers of thegastrointestinal tract (for example, esophageal cancer and pancreaticcancer), prostate cancer, kidney cancer, liver cancer, bladder cancer,cervical cancer, uterine cancer, testicular cancer, and ovarian cancer;dermatological conditions, such as acne vulgaris.

In yet another aspect, the present invention provides methods of using acompound or composition of the invention as an anorectic.

The present invention further provides pharmaceutical compositionscomprising a therapeutically effective amount of a pharmacologicallyactive compound of the instant invention, alone or in combination withone or more pharmaceutically acceptable carriers.

The pharmaceutical compositions according to the invention are thosesuitable for enteral, such as oral or rectal; transdermal and parenteraladministration to mammals, including man, for the treatment ofconditions mediated by DGAT1 activity. Such conditions include impairedglucose tolerance, Type 2 diabetes and obesity.

Thus, the pharmacologically active compounds of the invention may beemployed in the manufacture of pharmaceutical compositions comprising aneffective amount thereof in conjunction or admixture with excipients orcarriers suitable for either enteral or parenteral application.Preferred are tablets and gelatin capsules comprising the activeingredient together with:

a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol,cellulose and/or glycine;

b) lubricants, e.g., silica, talcum, stearic acid, its magnesium orcalcium salt and/or polyethyleneglycol; for tablets also

c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose and orpolyvinylpyrrolidone; if desired

d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt,or effervescent mixtures; and/or

e) absorbants, colorants, flavors and sweeteners.

Injectable compositions are preferably aqueous isotonic solutions orsuspensions, and suppositories are advantageously prepared from fattyemulsions or suspensions.

Said compositions may be sterilized and/or contain adjuvants, such aspreserving, stabilizing, wetting or emulsifying agents, solutionpromoters, salts for regulating the osmotic pressure and/or buffers. Inaddition, they may also contain other therapeutically valuablesubstances. Said compositions are prepared according to conventionalmixing, granulating or coating methods, respectively, and contain about0.1-75%, preferably about 1-50%, of the active ingredient.

Suitable formulations for transdermal application include atherapeutically effective amount of a compound of the invention withcarrier. Advantageous carriers include absorbable pharmacologicallyacceptable solvents to assist passage through the skin of the host.Characteristically, transdermal devices are in the form of a bandagecomprising a backing member, a reservoir containing the compoundoptionally with carriers, optionally a rate controlling barrier todeliver the compound of the skin of the host at a controlled andpredetermined rate over a prolonged period of time, and means to securethe device to the skin.

Accordingly, the present invention provides pharmaceutical compositionsas described above for the treatment of conditions mediated by DGAT1activity, preferably, impaired glucose tolerance, Type 2 diabetes andobesity.

The pharmaceutical compositions may contain a therapeutically effectiveamount of a compound of the invention as defined above, either alone orin a combination with another therapeutic agent, e.g., each at aneffective therapeutic dose as reported in the art. Such therapeuticagents include:

a) antidiabetic agents, such as insulin, insulin derivatives andmimetics; insulin secretagogues such as the sulfonylureas, e.g.,Glipizide, glyburide and Amaryl; insulinotropic sulfonylurea receptorligands such as meglitinides, e.g., nateglinide and repaglinide; proteintyrosine phosphatase-1B (PTP-1B) inhibitors such as PTP-112; GSK3(glycogen synthase kinase-3) inhibitors such as SB-517955, SB-4195052,SB-216763, NN-57-05441 and NN-57-05445; RXR ligands such as GW-0791 andAGN-194204; sodium-dependent glucose cotransporter inhibitors such asT-1095; glycogen phosphorylase A inhibitors such as BAY R3401;biguanides such as metformin; alpha-glucosidase inhibitors such asacarbose; GLP-1 (glucagon like peptide-1), GLP-1 analogs such asExendin-4 and GLP-1 mimetics; and DPPIV (dipeptidyl peptidase IV)inhibitors such as vildagliptin;

b) hypolipidemic agents such as 3-hydroxy-3-methyl-glutaryl coenzyme A(HMG-CoA) reductase inhibitors, e.g., lovastatin, pitavastatin,simvastatin, pravastatin, cerivastatin, mevastatin, velostatin,fluvastatin, dalvastatin, atorvastatin, rosuvastatin and rivastatin;squalene synthase inhibitors; FXR (famesoid X receptor) and LXR (liver Xreceptor) ligands; cholestyramine; fibrates; nicotinic acid bile acidbinding resins such as cholestyramine; fibrates; nicotinic acid andother GPR109 agonists; cholesterol absorption inhibitors such asezetimibe; CETP inhibitors (cholesterol-ester-transfer-proteininhibitors), and aspirin;

c) anti-obesity agents such as orlistat, sibutramine and CannabinoidReceptor 1 (CB1) antagonists e.g. rimonabant; and

d) anti-hypertensive agents, e.g., loop diuretics such as ethacrynicacid, furosemide and torsemide; angiotensin converting enzyme (ACE)inhibitors such as benazepril, captopril, enalapril, fosinopril,lisinopril, moexipril, perinodopril, quinapril, ramipril andtrandolapril; inhibitors of the Na-K-ATPase membrane pump such asdigoxin; neutralendopeptidase (NEP) inhibitors; ACE/NEP inhibitors suchas omapatrilat, sampatrilat and fasidotril; angiotensin II antagonistssuch as candesartan, eprosartan, irbesartan, losartan, telmisartan andvalsartan, in particular valsartan; renin inhibitors such as ditekiren,zankiren, terlakiren, aliskiren, RO 66-1132 and RO-66-1168; β-adrenergicreceptor blockers such as acebutolol, atenolol, betaxolol, bisoprolol,metoprolol, nadolol, propranolol, sotalol and timolol; inotropic agentssuch as digoxin, dobutamine and milrinone; calcium channel blockers suchas amlodipine, bepridil, diltiazem, felodipihe, nicardipine, nimodipine,nifedipine, nisoldipine and verapamil; aldosterone receptor antagonists;and aldosterone synthase inhibitors.

e) agonists of peroxisome proliferator-activator receptors, such asfenofibrate, pioglitazone, rosiglitazone, tesaglitazar, BMS-298585,L-796449, the compounds specifically described in the patent applicationWO 2004/103995 i.e. compounds of examples 1 to 35 or compoundsspecifically listed in claim 21, or the compounds specifically describedin the patent application WO 03/043985 i.e. compounds of examples 1 to 7or compounds specifically listed in claim 19 and especially(R)-1-{4-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxylicor a salt thereof.

In each case in particular in the compound claims and the final productsof the working examples, the subject matter of the final products, thepharmaceutical preparations and the claims are hereby incorporated intothe present application by reference to these publications and patentapplications.

Thus the invention covers pharmaceutical compositions comprising;

i) a compound according to any of claims 1 to 24, and

ii) at least one compound selected from

-   -   a) antidiabetic agents,    -   b) hypolipidemic agents,    -   c) anti-obesity agents,    -   d) anti-hypertensive agents,    -   e) agonists of peroxisome proliferator-activator receptors,

ii) one or more pharmaceutically acceptable carriers.

Other specific anti-diabetic compounds are described by Patel Mona inExpert Opin Investig Drugs, 2003, 12(4), 623-633, in the figures 1 to 7,which are herein incorporated by reference. A compound of the presentinvention may be administered either simultaneously, before or after theother active ingredient, either separately by the same or differentroute of administration or together in the same pharmaceuticalformulation.

The structure of the therapeutic agents identified by code numbers,generic or trade names may be taken from the actual edition of thestandard compendium “The Merck Index” or from databases, e.g., PatentsInternational (e.g. IMS World Publications). The corresponding contentthereof is hereby incorporated by reference.

Accordingly, the present invention provides pharmaceutical compositionscomprising a therapeutically effective amount of a compound of theinvention in combination with a therapeutically effective amount ofanother therapeutic agent, preferably selected from anti-diabetics,hypolipidemic agents, anti-obesity agents or anti-hypertensive agents,most preferably from antidiabetics or hypolipidemic agents as describedabove.

The present invention further relates to pharmaceutical compositions asdescribed above for use as a medicament.

The present invention further relates to use of pharmaceuticalcompositions or combinations as described above for the preparation of amedicament for the treatment of conditions mediated by DGAT1 activity,preferably, impaired glucose tolerance, Type 2 diabetes and obesity.

Thus, the present invention also relates to a compound as defined in theclaims and described above for use as a medicament; to the use of acompound as defined in the claims and described above for thepreparation of a pharmaceutical composition for the prevention and/ortreatment of conditions mediated by DGAT1 activity, and to apharmaceutical composition for use in conditions mediated by DGAT1activity comprising a compound as defined in the claims and describedabove, or a pharmaceutically acceptable salt thereof, in associationwith a pharmaceutically acceptable diluent or carrier therefore.

The present invention further provides a method for the preventionand/or treatment of conditions mediated by DGAT1 activity, whichcomprises administering a therapeutically effective amount of a compoundof the present invention.

A unit dosage for a mammal of about 50-70 kg may contain between about 1mg and 1000 mg, advantageously between about 5-500 mg of the activeingredient. The therapeutically effective dosage of active compound isdependent on the species of warm-blooded animal (mammal), the bodyweight, age and individual condition, on the form of administration, andon the compound involved.

In accordance with the foregoing the present invention also provides atherapeutic combination, e.g., a kit, kit of parts, e.g., for use in anymethod as defined herein, comprising a compound as defined in the claimsand described above, or a pharmaceutically acceptable salt thereof, tobe used-concomitantly or in sequence with at least one pharmaceuticalcomposition comprising at least another therapeutic agent, preferablyselected from anti-diabetic agents, hypolipidemic agents, anti-obesityagents and anti-hypertensive agents, or a pharmaceutically acceptablesalt thereof. The kit may comprise instructions for its administration.The combination can be a fixed combination (e.g. in the samepharmaceutical composition) or a free combination (e.g. in separatepharmaceutical compositions).

Similarly, the present invention provides a kit of parts comprising: (i)a pharmaceutical composition of the invention; and (ii) a pharmaceuticalcomposition comprising a compound selected from an anti-diabetic, ahypolipidemic agent, an anti-obesity agent and an anti-hypertensiveagent, or a pharmaceutically acceptable salt thereof, in the form of twoseparate units of the components (i) to (ii).

Likewise, the present invention provides a method as defined abovecomprising co-administration, e.g., concomitantly or in sequence, of atherapeutically effective amount of a compound as defined in the claimsand described above, or a pharmaceutically acceptable salt thereof, anda second drug substance, said second drug substance being ananti-diabetic, a hypolipidemic agent, an anti-obesity agent or ananti-hypertensive agent, e.g., as indicated above.

Preferably, a compound of the invention is administered to a mammal inneed thereof.

Preferably, a compound of the invention is used for the treatment of adisease which responds to modulation of the DGAT1 activity.

Preferably, the condition associated with DGAT1 activity is selectedfrom impaired glucose tolerance, Type 2 diabetes and obesity.

Finally, the present invention provides a method or use which comprisesadministering a compound as defined in the claims and described above incombination with a therapeutically effective amount of an anti-diabeticagent, a hypolipidemic agent, an anti-obesity agent or ananti-hypertensive agent.

Ultimately, the present invention provides a method or use whichcomprises administering a compound as defined in the claims anddescribed above in the form of a pharmaceutical composition as describedherein.

As used throughout the specification and in the claims, the term“treatment” embraces all the different forms or modes of treatment asknown to those of the pertinent art and in particular includespreventive, curative, delay of progression and palliative treatment.

The above-cited properties are demonstrable in vitro and in vivo testsusing advantageously mammals, e.g., mice, rats, dogs, monkeys orisolated organs, tissues and preparations thereof. Said compounds can beapplied in vitro in the form of solutions, e.g., preferably aqueoussolutions, and in vivo either enterally, parenterally, advantageouslyintravenously, e.g., as a suspension or in aqueous solution. The dosagein vitro may range between about 10⁻² molar and 10⁻⁹ molarconcentrations. A therapeutically effective amount in vivo may rangedepending on the route of administration, between about 0.1 mg/kg and1000 mg/kg, preferably between about 1 mg/kg and 100 mg/kg.

The activity of compounds according to the invention may be assessed bythe following methods or methods well-described in the art.

The enzyme preparation used in this assay is a membrane preparation fromSf9 cells overexpressing human (His)₆DGAT1. During all steps sampleswere chilled to 4° C. Sf9 cells expressing human (His)₆DGAT1 were thawedat RT and re-suspended at a 10:1 ratio (mL buffer/g of cells) in 50 mMHEPES, 1× Complete Protease Inhibitor, pH 7.5.

The re-suspended pellet was homogenized for 1 min using a Brinkman PT10/35 homogenizer with a 20 mm generator. Cells were lysed using AvestinEmulsiflex (chilled to 4° C.) at 10000-15000 psi. Lysate was centrifugedat 100,000×g for 1 h at 4° C. Supernatant was removed and pellets werere-suspended in 50 mM HEPES, 1× Complete Protease Inhibitor, pH 7.5 at1/6 the volume of supernatant. Re-suspended pellets were pooled andhomogenized with 10 strokes of a Glas-Col motor driven teflon pestle onsetting 70. The protein concentration of the membrane preparation wasquantified using BCA protein assay with 1% SDS. The membrane preparationwas aliquoted, frozen on dry ice, and stored at −80° C.

For 50 mL, 25 mL of 0.2 M HEPES stock buffer, 0.5 mL of 1 M MgCl₂ (5 mMfinal concentration), and 24.5 mL of milli-Q H₂O are added to the 55 mLWheaton Potter-Elvehjem homogenizer. Enzyme preparation (0.1 mL) isadded to buffer and the mixture is homogenized with 5 strokes on iceusing the Glas-Col variable speed homogenizer system on setting 70.

For 50 mL, 0.5 mL 10 mM diolein is added to 9.5 mL of EtOH in a 50 mLFalcon screw cap conical centrifuge tube. Five mL of 10 mM sodiumacetate pH 4.5 is added followed by 0.5 mL of 10 mM oleoyl-CoA. Finally,the remaining 4.5 mL of 10 mM sodium acetate pH 4.5 is added followed by30 mL of milli-Q H₂O. The solution should be gently agitated by hand toinduce mixing. The final concentrations of EtOH and sodium acetate are20% and 2 mM, respectively.

Dry compounds are dissolved in the appropriate volume of DMSO to a finalconcentration of 10 mM. A 10-point, 3-fold dose response is used toevaluate compound potency. All dilutions are performed in DMSO in aGreiner 384-well microplate.

1. 2 μL of compound in DMSO is added to the appropriate wells. 2 μL ofDMSO is added to 100% activity and 100% inhibition controls.

2. 25 μL of enzyme mix is added to all wells and plate(s) are incubatedfor 10 min at RT.

3. 10 μL of 20% acetic acid quench is added to 100% inhibition controlwells. Plate(s) are vortexed using Troemner multi-tube vortexer (setting7 for 10 sec).

4. 25 μL of substrate mix is added to all wells. Plate(s) are vortexedusing Troemner multi-tube vortexer (setting 7 for 10 sec). Plate(s) areincubated for 30 min at RT.

5. 10 μL of 20% acetic acid quench is added to all wells. Plate(s) arevortexed using Troemner multi-tube vortexer (setting 7 for 10 sec).

6. 50 μL of 1-butanol w/ glyceryl tripalmitoleate internal standard isadded to all wells.

7. Plate(s) are sealed with super pierce strong plate sealer using thethermo-sealer.

8. Plate(s) are vortexed using Troemner multi-tube vortexer (setting 10for 5 min).

9. Plate(s) are centrifuged at 162×g (1000 rpm for GH-3.8 rotor) for 5min using Beckman GS-6R tabletop centrifuge.

Samples were analyzed by LC/MS/MS using a Waters 1525μ LC and QuattroMicro API MS. Where indicated, tripalmitolein was used as an internalstandard to control for instrument variation.

Data is converted to % inhibition prior to curve fitting using thefollowing equation:

${\% \mspace{14mu} {Inhibition}} = {\frac{\begin{pmatrix}{{{response}\mspace{14mu} {compound}} -} \\{{response}\mspace{14mu} 100\% \mspace{14mu} {inhibition}\mspace{14mu} {control}}\end{pmatrix}}{\begin{pmatrix}{{{response}\mspace{14mu} 100\% \mspace{14mu} {activity}\mspace{14mu} {control}} -} \\{{response}\mspace{14mu} 100\% \mspace{14mu} {inhibition}\mspace{14mu} {control}}\end{pmatrix}} \times 100}$

Using the method described above, the compounds of the present inventionwere shown to possess inhibitory activity with IC50 values ranging from0.001 uM to 100 uM.

Table 1 shows the inhibitory activity (IC₅₀ values) of representativecompounds to human DGAT1.

Example IC₅₀ (μM) 3-15 0.6 3-25 1.4 3-33 11 6-29 0.23

Methods of Preparation

Compounds of the present invention may be prepared from commerciallyavailable reagents employing general synthetic techniques known to thoseskilled in the art. Outlined below are reaction schemes suitable forpreparing such compounds. Further exemplification is found in thespecific examples provided.

As shown in Scheme 1, compounds of the present invention where B is apyrimidine ring may be prepared from a suitably functionalized startingmaterial. For instance, in the synthetic sequence shown above, Y may bea halogen atom, toluenesulfonate, methanesulfonate, ortrifluoromethanesulfonate. The amine derivative (described above asR₁NH2) may be condensed with the functionalized pyrimidine in thepresence of acid (i.e., concentrated HCl, sulfuric acid, or ammoniumchloride) or base (sodium hydride, alkyl lithiums, lithium amides,triethylamine, DBU), in an organic or aqueous solvent, typically atelevated temperature, to afford the aminopyrimidine adduct. Thistransformation may also be facilitated through transition metalcatalysis; for example, copper or palladium reagents which may becomplexed with additional ligands (for example, phosphine ligands suchas BINAP, X-Phos, tri-t-butyl phosphine or amino ligands such asN,N-cyclohexane diamine derivatives) in the presence of a base mayfacilitate the amino pyrimidine synthesis.

The resulting amino pyrimidine may then be coupled to a suitablyfunctionalized arene intermediate. For example, where X is a halogenatom, toluenesulfonate, methanesulfonate, or trifluoromethanesulfonate,W in the scheme above may be an organometallic substituent (for example,boron, tin, zinc, magnesium) that may be subjected to transition-metalcross coupling conditions known to those skilled in the art. Suchcross-coupling events may be promoted by palladium complexes such asPd(OAc)₂ or Pd(PPh₃)₄ that may be additionally supported by ligands(phosphines, N-heterocyclic carbenes). These reactions may be conductedin the presence of inorganic bases such as sodium carbonate or potassiumacetate under aqueous or anhydrous conditions.

For cases where Q is a protected carboxylic acid derivative, hydrolysismay be promoted by aqueous bases such as lithium hydroxide oralternatively under acidic conditions to afford the final compound.

As shown in Scheme 2, compounds in the current invention where B is athiazole ring may be prepared starting from the appropriate phenylderivative. Acylation with an activated carboxylic acid derivative (acidchloride or acid bromide) in the presence of a Lewis acid such asaluminium trichloride may afford the bromo acetophenone derivative shownabove. Condensation of this intermediate with a suitably functionalizedthiourea in the presence of a base such as potassium carbonate ortriethylamine may produce the amino thiazole shown above.

For compounds of the current invention where B is an oxazole ring, thegeneral synthetic sequence described in Scheme 3 may be used. Conversionof the bromo acetophenone derivative to the corresponding azidointermediate may occur via reaction of sodium or lithium azide in anorganic solvent which may or may not contain water. The azido ketoneintermediate may then be treated with a triaryl- or trialkylphosphine(such as triphenylphosphine) in the presence of an isothiocyanate toafford the corresponding amino oxazole. This cyclization often requiresheating, and is described by Dhar et at in Bioorg. Med. Chem. Lett 12(2002) 3125-3128.

For compounds of the current invention where B is a pyridine ring, thegeneral synthetic sequence described in Scheme 4 may be used. An aminoderivative may be reacted with the appropriate pyridine derivative toafford the corresponding amino pyridine intermediate. For example, whenY is a suitably-placed leaving group (i.e., in the 2- or 4-position)such as halogen atom, toluenesulfonate, methansulfonate, ortrifluoromethanesulfonate, the amino derivative R₁NH₂ may be reacted inthe presence of add (such as HCl or sulphuric acid) or base (such assodium hydride, triethylamine, or DBU) to afford the amino pyridineintermediate. The use of transition metals such as palladium or coppermay also facilitate this transformation, regardless of where Y isdisposed. Alternatively, copper salts may mediate the process where Y isa boronic acid or ester derivative [See Tet. Lett. (1998) vol. 39, p.2941]. The resulting amino pyridine derivative may then be coupled tothe aryl-W intermediate above using transition metal-catalyzedcross-coupling methodology. For instance, where W is a boronicacid/ester, trialkyltin, or trialkylsilane, the appropriate aryl-Xpartner where X is a halogen atom or sulfonate may be reacted in thepresence of a transition metal such as palladium with or without asupporting ligand to effect this carbon-carbon bond construction.Alternatively, W and X may be reversed in this bond disconnection.

Alternatively, the sequence above may be re-ordered as follows:

In the above scheme, W may be a boronic ester or suitable equivalent, Xmay be a halogen or appropriate sulfonate, and Y may be a nitrogenprecursor such as nitro or protected nitrogen such as NHBoc. Y may thenbe elaborated to the corresponding amino derivative, which may then becoupled with the appropriate R1-X derivative under acidic, basic, ormetal-promoted conditions as described above.

For compounds of the current invention where B is a pyridazine ring, thesynthetic sequence shown in Scheme 5 may be applied. A difunctionalizedpyridazine intermediate, for instance 3,6-dichloropyridazine, may bereacted with an amino nucleophile R₁NH₂ in the presence of acid (such asHCl or sulphuric acid) or base (such as sodium hydride, triethylamine,or DBU) to afford the amino pyridazine intermediate. The use oftransition metals such as palladium or copper may also facilitate thistransformation, regardless of where X and Y are disposed. The resultingamino pyridazine derivative may then be coupled to the aryl-Wintermediate above using transition metal-catalyzed cross-couplingmethodology. For instance, where W is a boronic acid/ester, trialkyltin,or trialkylsilane, the appropriate aryl-X partner where X is a halogenatom or sulfonate may be reacted in the presence of a transition metalsuch as palladium with or without a supporting ligand to effect thiscarbon-carbon bond construction. Alternatively, W and X may be reversedin this bond disconnection.

The compounds of the current invention where B is a pyridazine ring mayalso be prepared by the synthetic sequence shown in Scheme 6. Acylationof the starting arene derivative with the appropriate carboxylic acidderivative (i.e., an acid chloride) in the presence of a Lewis acid suchas aluminium trichloride may produce the acetophenone derivative shown.Construction of the pyridazone ring may be effected by analogy toliterature precedence (Synthesis (1993) p. 334). Activation of thepyridazone intermediate via the chloro or bromo pyridazine may beaccomplished via phosphorous oxychloride, phosphorous bromide, orequivalent activating reagent. Substitution with the amine R₁—NH₂ thenmay occur under acidic, basic, or transition-metal promoted conditions.

For compounds of the current invention where B is a pyrazine ring, thesynthetic sequence shown in Scheme 7 may be applied. A difunctionalizedpyrazine intermediate may be reacted with an amino nucleophile R₁NH₂ inthe presence of acid (such as HCl or sulphuric acid) or base (such assodium hydride, triethylamine, or DBU) to afford the amino pyridineintermediate. The use of transition metals such as palladium or coppermay also facilitate this transformation, regardless of where X and Y aredisposed. The resulting amino pyrazine derivative may then befunctionalized with an X group such as halogen or sulfonate, and thencoupled to the aryl-W intermediate above using transitionmetal-catalyzed cross-coupling methodology. For instance, where W is aboronic acid/ester, trialkyltin, or trialkylsilane, the appropriatearyl-X partner may be reacted in the presence of a transition metal suchas palladium with or without a supporting ligand to effect thiscarbon-carbon bond construction. Alternatively, W and X may be reversedin this bond disconnection.

EXAMPLES

The following Examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. If not mentionedotherwise, all evaporations are performed under reduced pressure,preferably between about 50 mmHg and 100 mmHg. The structure of finalproducts, intermediates and starting materials is confirmed by standardanalytical methods, e.g., microanalysis, melting point (m.p.) andspectroscopic characteristics, e.g., MS, IR and NMR. Abbreviations usedare those conventional in the art.

HPLC Conditions:

A: Inertsil 4.6 mm×5 cm C8-3 column, 10 to 90% Acetonitrile in 5 mMammonium formate, 2 min gradient, 4 mL/min, 50 degrees centigrade

B: Inertsil 4.6 mm×5 cm C8-3 column, 40 to 90% Acetonitrile in 5 mMammonium formate, 2 min gradient, 4 mL/min, 50 degrees centigrade

C: Inertsil 4.6 mm×5 cm C8-3 column, 40 to 90% Acetonitrile in 0.1%acetic acid, 2 min gradient, 4 mL/min, 50 degrees centigrade

D: Column: Atlantis C18 (Waters, Inc.), 15 cm×4.6 mm×5 μm

-   -   Column temperature: Ambient    -   Flow rate: 1.4 mL/min    -   Injection volume: 3.0 μL    -   Gradient: A=0.1% Trifluoroacetic Acid (TFA) in Water        -   B=0.05% Trifluoroacetic Acid (TFA) in Acetonitrile        -   0-95% B in 19.0 min, 1.8 min hold

E: Gemini C18 4.6×50 mm, 5 um particle size; 5-100% ACN/H2O+5 mM NH40H/8min

Example 1-1(4-{4-[2-(3-Fluorophenylamino)-pyrimidin-5-yl]-phenyl}-cyclohexyl)-aceticacid

A. (5-Bromopyrimidin-2-yl)-(3-fluorophenyl)-amine

In a microwave vial is added 3-fluorophenylamine (0.293 mL, 2.58 mmol),5-bromo-2-chloropyrimidine (500 mg, 2.58 mmol), EtOH (10 mL) andconcentrated HCl (0.2 mL). The reaction mixture is then heated at 50° C.for 15 min. Water (20 mL) is added and it is extracted with EtOAc. Theorganic layer is washed with NaHCO₃, dried with Na₂SO₄ and concentrated.The residue is purified by column chromatography to give the titlecompound: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.83-6.88 (m, 1 H)7.24-7.26 (m, 1H) 7.28 (br. s., 1H) 7.34-7.40 (m, 1H)7.74 (dt, J=11.37,2.27 Hz, 1H) 8.56 (s, 2H); (M+H)+ 269.9.

B.(4-{4-[2-(3-Fluorophenylamino)-pyrimidin-5-yl]-phenyl}-cyclohexyl)-aceticacid methyl ester

The mixture of (5-bromopyrimidin-2-yl)-(3-fluorophenyl)-amine (75 mg,0.28 mmol),{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclohexyl}-aceticacid methyl ester (Patent WO2004 047755) (100 mg, 0.28 mmol), PdCl₂dppf(12 mg, 0.014 mmol), sodium carbonate (2M solution, 0.35 mL) and DME (2mL) is heated in a microwave at 125° C. for 15 Min. The reaction mixtureis extracted with EtOAc, washed with NH₄Cl solution. The organic phaseis dried with MgSO₄, filtered and it is used directly in the next step:(M+H)+ 420.3.

C.(4-{4-[2-(3-Fluorophenylamino)-pyrimidin-5-yl]-phenyl}-cyclohexyl)-aceticacid

To a solution of(4-{4-[2-(3-fluorophenylamino)-pyrimidin-5-yl]-phenyl}-cyclohexyl)-aceticacid methyl ester (crude from above) in DMF (2.5 mL) is added LiOH (10%solution, 1 mL) and the reaction mixture is heated at 60° C. for 1.5 h.The mixture is then subjected to HPLC purification to give the titlecompound: ¹H NMR (400 MHz, DMSO-d6) δ 1.09-1.15 (m, 1H) 1.50 (td,J=12.44, 9.98 Hz, 1H) 1.63 (d, J=5.31 Hz, 6H) 2.37 (d, J=7.58 Hz, 2H)6.76 (td, J=8.21, 2.27 Hz, 1H) 7.28-7.39 (m, 4H) 7.52 (dd, J=8.34, 1.26Hz, 1H) 7.65 (s, 1H) 7.63 (t, J=4.04 Hz, 2H) 7.87 (d, J=12.38 Hz, 1H)8.84-8.86 (m, 2H) 9.99 (s, 1H); (M+H)⁺=406.2.

Alternatively, the methyl ester can be dissolved in THF and treated withaqueous sodium hydroxide (4 equiv). The mixture can then be stirred at50 degrees for 12 hours, at which point water may be added and most ofthe organic solvent may be removed under reduced pressure. Addition ofacetonitrile followed by cooling may yield a precipitate which can beisolated by filtration to afford the title compound as the correspondingsodium salt.

The examples below were synthesized in analogous fashion using boronateesters (in step B) that are known in the literature: for example,2,2-dimethyl-4-oxo-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-butyricacid (patent US 2004 0224997) and(1S,2S)-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoyl]-cyclopentanecarboxylicacid (patent US 2004 0224997).

MS Example Chemical Name LC rt Method (M + H)⁺ 1-2{4-[4-(2-Phenylaminopyrimidin- 1.44 A 388.2 5-yl)-phenyl]-cyclohexyl}-acetic acid 1-3 4-{4-[2-(3-Fluorophenylamino)- 1.31 A 394.1pyrimidin-5-yl]-phenyl}- 2,2-dimethyl-4-oxo-butyric acid 1-4(1S,2S)-2-{4-[2-(3- 1.28 A 406.1 Fluorophenylamino)-pyrimidin-5-yl]-benzoyl}- cyclopentanecarboxylic acid 1-5 (1S,2S)-2-{4-[2-(3- 1.33A 422.1 Chlorophenylamino)-pyrimidin- 5-yl]-benzoyl}-cyclopentanecarboxylic acid

Example 1-6(4-{4-[2-(6-Trifluoromethyl-pyridin-3-ylamino)-pyrimidin-5-yl]-phenyl}-cyclohexyl)-aceticacid

(4-[4-(2-Chloro-pyrimidin-5-yl)-phenyl]-cyclohexyl}-acetic acid methylester

PdCl₂dppf (120 mg, 0.140 mmol) is added to a degassed mixture of{4-[4(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclohexyl}-aceticacid methyl ester (1.00 g, 2.79 mmol), 5-bromo-2-chloro-pyrimidine (540mg, 2.79 mmol), 2 M Na₂CO₃ (2.8 mL), and DME (7.5 mL). The mixture issealed in a glass tube and heated to 120° C. for 20 min by microwaveirradiation. The reaction is diluted with EtOAc (150 mL), and theresulting suspension filtered. The filtrate is extracted with 1 N HCl(25 mL) and the organic layer dried over Na₂SO₄. Concentration followedby silica gel chromatography (20% EtOAc/Hexanes) affords{4-[4-(2-chloro-pyrimidin-5-yl)-phenyl]-cyclohexyl}-acetic acid methylester as a white solid: 1H NMR (400 MHz, CHLOROFORM-d) δppm 1.14-1.27(m, 2H) 1.49-1.61 (m, 2H) 1.86-1.98 (m, 5H) 2.28 (d, J=6.82 Hz, 2H) 2.56(tt, J=12.22, 3.19 Hz, 1H) 3.70 (s, 3H) 7.37 (d, J=8.08 Hz, 2H) 7.49 (d,J=8.34 Hz, 2H) 8.81 (s, 2H); (M+H)+ 345.1.

(4-{4-[2-(6-Trifluoromethyl-pyridin-3-ylamino)-pyrimidin-5-yl]-phenyl)-cyclohexyl}-aceticacid. To a glass vial add 6-trifluoromethyl-pyridin-3-ylamine (35 mg,0.217 mmol), {4-[4-(2-chloro-pyrimidin-5-yl)-phenyl]-cyclohexyl}-aceticacid methyl ester (50 mg, 0.145 mmol), Pd(OAc)₂(5 mg, 5% mol), X-Phos (7mg, 10% mol), and Cs₂CO₃ (118 mg, 0.363 mmol). Flush with N₂. Add tBuOH(0.25 mL), toluene (0.75 mL), and seal the tube. The reaction mixture isheated to 150° C. for 30 min by microwave irradiation. The reaction isdiluted with EtOAc and filtered. The filtrate is concentrated andchromatographed on silica gel (25-50% EtOAc/Hexanes) to afford(4-{4-[2-(6-Trifluoromethyl-pyridin-3-ylamino)-pyrimidin-5-yl]-phenyl}-cyclohexyl)-aceticacid methyl ester as 90% pure.(4-{4-[2-(6-Trifluoromethyl-pyridin-3-ylamino)-pyrimidin-5-yl]-phenyl}-cyclohexyl)-aceticacid methyl ester (45 mg, 0.096 mmol) is taken up in DMF (1.5 mL) and 4M LiOH (0.5 mL) and stirred at room temperature for 16 h. The reactionis heated to 50° C. for 12 h and then heated to 70° C. for 8 h. Thereaction is diluted with 1 N HCl (2 mL) and H₂O (2 mL). The precipitateis collected by filtration and purified by HPLC (Xterra C8 30×100 mm,22-50% ACN/H₂O+ 5 mM NH4OH) to afford(4-{4-[2-(6-Trifluoromethyl-pyridin-3-ylamino)-pyrimidin-5-yl]-phenyl}-cyclohexyl)-aceticacid as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.05-1.18 (m, 2H)1.43-1.56 (m, J=12.95, 12.66, 12.66, 3.16 Hz, 2H) 1.68-1.87 (m, 6H) 2.08(d, J=6.57 Hz, 2H) 7.35 (d, J=8.34 Hz, 2H) 7.65 (d, J=8.34 Hz, 2H) 7.85(d, J=8.59 Hz, 1H) 8.55 (dd, J=8.59, 2.02 Hz, 1H) 8.91 (s, 2H) 9.06 (d,J=2.27 Hz, 1H) 10.42 (s, 1H); (M+H)+ 457.0.

Using analogous procedures, the following compounds may also beprepared:

Example Name LC rt Method (M + H)+ Ex. 1-7 (4-{4-[2-(5-Chloro-pyridin-2-13 D 423.1 ylamino)-pyrimidin-5-yl]- phenyl}-cyclohexyl)-acetic acid

Example 2-1(4-{4-[2-(3-Methoxyphenylamino)-thiazol-4-yl]-phenyl}-cyclohexyl)-aceticacid

A. {4-[4-(2-Bromoacetyl)-phenyl]-cyclohexyl}-acetic acid ethyl ester

To a solution of (4-phenylcyclohexyl)-acetic acid ethyl ester (10.0 g,40.6 mmol) (patent WO2004 047755) in DCM (100 mL) at 0° C. is addedAlCl₃ (9.94 g, 74 mmol) portionwise. After it is stirred at −1.8° C. for10 min, bromoacetyl bromide (3.59 mL, 40.6 mmol) is added dropwise over2 min. The reaction mixture is allowed to stir at ˜1.8° C. for 2 h. Itis then poured slowly to water/ice mixture (200 mL) and stirred for 30min. The mixture is extracted with DCM (2×50 mL). The organic phase isseparated and washed with NaHCO₃ (3×100 mL), and brine (3×100 mL), driedwith Na₂SO₄, concentrated and dried under high vacuum to give the titlecompound (12.8 g) as a yellow solid: 1H NMR (400 MHz, CHLOROFORM-d) δppm 1.05-1.17 (m, 2H) 1.20 (t, J=8.00 Hz, 3H) 1.39-1.51 (m, 2H)1.56-1.68 (m, 1H) 1.76-1.87 (m, 4H) 2.18 (d, J=4.29 Hz, 2H) 2.48 (td,J=12.32, 2.65 Hz, 1H) 4.08 (q, J=7.24 Hz, 2H) 4.35 (s, 2H) 7.25 (d,J=8.34 Hz, 2H) 7.85(d, J=8.59 Hz, 2H).

B.(4-{4-[2-(3-Methoxyphenylamino)-thiazol-4-yl]-phenyl}-cyclohexyl)-aceticacid ethyl ester

To a solution of {4-[4-(2-bromoacetyl)-phenyl]cyclohexyl}-acetic acidethyl ester (100 mg, 0.272 mmol) in EtOH/THF (4:1 v/v, 5 mL) is added3-methoxyphenylthiourea (99.6 mg, 0.272 mmol) and Na₂CO₃ (58 mg, 0.545mmol). The reaction mixture is allowed to stir at 50° C. for 3 h. Thereaction mixture is used directly in the next step: (M+H)+ 451.1.

C.(4-{4-[2-(3-Methoxyphenylamino)-thiazol-4-yl]-phenyl}-cyclohexyl)-aceticacid. General Saponification Procedure

To the reaction mixture of(4-{4-[2-(3-methoxyphenylamino)-thiazol-4-yl]-phenyl}-cyclohexyl)-aceticacid ethyl ester from step B is added LiOH (10% solution, 1 mL). It isthen heated at 50° C. for 18 h. The mixture is then acidified with HClsolution (1 N) to pH=5. The resulting solid is filtered and dried underhigh vacuum to give the title compound (26.8 mg) as a solid; ¹H NMR (400MHz, DMSO-d6) δ ppm 0.96-1.07 (m, 2H) 1.31-1.43 (m, 2H) 1.50-1.52 (m,1H) 1.58-1.64 (m, 1H) 1.71 (d, J=9.60 Hz, 4H) 2.03 (d, J=6.57 Hz, 2H)2.27 (br. s., 1H) 3.67 (s, 3H) 6.43 (dd, J=7.83, 1.77 Hz, 1H) 7.03 (dd,J=7.20, 0.88 Hz, 1H) 7.09-7.20 (m, 4H) 7.44 (br. s., 1H) 7.70 (d, J=8.08Hz, 2H) 10.13 (br. s., 1H); MS (M+H)⁺=423.2.

Alternatively, the methyl ester can be dissolved in THF and treated withaqueous sodium hydroxide (4 equiv). The mixture can then be stirred at50 degrees for 12 hours, at which point water may be added and most ofthe organic solvent may be removed under reduced pressure. Addition ofacetonitrile followed by cooling may yield a precipitate which can beisolated by filtration to afford the title compound as the correspondingsodium salt.

The following compounds are prepared in analogous fashion:

MS (M + Example Chemical Name LC rt Method H)⁺ 2-2(4-{4-[2-(3-Fluorophenylamino)- 1.53 A 411.2 thiazol-4-yl]-phenyl}-cyclohexyl)-acetic acid 2-3 (4-{4-[2-(2-Chlorophenylamino)- 1.65 A 427.1thiazol-4-yl]-phenyl}- cyclohexyl)-acetic acid 2-4(4-{4-[2-(3-Cyanophenylamino)- 1.41 A 418.1 thiazol-4-yl]-phenyl}-cyclohexyl)-acetic acid 2-5 (4-{4-[2-(3-Trifluoro- 1.59 A 461.1methylphenylamino)-thiazol-4-yl]- phenyl}-cyclohexyl)-acetic acid

Example 2-6(4-{4-[2-(3-Fluorophenylamino)-thiazol-4-yl]-phenyl}-cyclohexyl)-aceticacid

A. [4-(4-Bromophenyl)-thiazol-2-yl]-(3-fluorophenyl)-amine

The title compound is prepared analogously to Example 2-1 step B using2-bromo-1-(4-bromophenyl)-ethanone and 3-fluorophenylthiourea: (M+H)+350.9.

B.2,2-Dimethyl-4-oxo-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-butyricacid

To a microwave vial is added4-(4-bromophenyl)-2,2-dimethyl-4-oxo-butyric acid (150 mg, 0.526 mmol),bis(pinacolato)diboron (160 mg, 0.631 mmol), KOAc (155 mg, 1.58 mmol)and PdCl₂dppf CH₂Cl₂(13 mg, 0.015 mmol). Then DME (2 mL) is added andthe mixture is sparged with nitrogen for 2 min. The vial is then sealedand heated in a microwave at 120° C. for 20 min. The reaction mixture isthen used directly in the next step: (M+H)+ 333.1.

C.(4-{4-[2-(3-Fluorophenylamino)-thiazol-4-yl]-phenyl}-cyclohexyl)-aceticacid

To a microwave vial is added[4-(4-bromophenyl)-thiazol-2-yl]-(3-fluorophenyl)-amine (92 mg, 0.26mmol),2,2-dimethyl-4-oxo-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-butyricacid (half of the crude from last step), sodium carbonate (2M solution,0.526 mL) and resin bound Pd(PPh₃)₄ (130 mg, 0.013 mmol). The reactionmixture is sparged with nitrogen for 2 min and then heated in amicrowave at 120° C. for 20 min. The resin is then filtered off and thefiltrate is concentrated. The residue is titrate with ether. Theresulting yellow solid is purified by reverse-phase preparative HPLC togive the title compound: 1H NMR (400 MHz, DMSO-D6) δ ppm 1.24 (s, 6H),2.49 (d, J=3.54 Hz, 4H), 3.34 (s, 8H), 6.73-6.82 (m, 1H), 7.05 (s, 2H),7.17 (s, 3H), 7.33 (s, 2H), 7.35-7.40 (m, 2H), 7.50 (s, 1H), 7.81-7.90(m, 5H), 8.04 (dd,J=8.34, 2.53 Hz, 4H), 10.56 (s, 1H); (M+H)⁺=475.0.

The following compounds are prepared in analogous fashion:

MS Example Chemical Name LC rt Method (M + H)⁺ 2-73-{4′-[2-(3-Fluorophenylamino)- 1.42 A 419.1thiazol-4-yl]-biphenyl-4-yl}- propionic acid 2-8{4′-[2-(3-Fluorophenylamino)- 1.35 A 405.1 thiazol-4-yl]-biphenyl-4-yl}-acetic acid

Example 3-1(4-{4-[2-(3-Chlorophenylamino)-oxazol-5-yl]-phenyl}-cyclohexyl)-aceticacid

A. (4-{4-(2-Azidoacetyl)-phenyl]-cyclohexyl}-acetic acid ethyl ester

To a solution of (4-{4-(2-bromoacetyl)-phenyl]-cyclohexyl}-acetic acidethyl ester (166 mg, 0.451 mmol) in acetone/water (4:1, v/v, 5 mL) isadded NaN₃ (44 mg, 0.676 mmol) and the mixture is stirred at ambienttemperature for 2 h. Water (10 mL) is added and EtOAc is used toextract. The organic phase is dried with MgSO₄, concentrated, and driedunder high vacuum to give the title compound (154 mg): 1H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.05-1.16 (m, 2H) 1.20 (t, J=7.07 Hz, 3H) 1.40-1.49(m, 2H) 1.84 (d, J=10.11 Hz, 4H) 1.76-1.87 (m, 1H) 2.17 (d, J=6.82 Hz,2H) 2.48 (tt,J=12.25, 3.03 Hz, 1H) 4.08 (q, J=7.16 Hz, 2H) 4.45 (s, 2H)7.25 (d, J=8.34 Hz, 2H) 7.76 (d, J=8.34 Hz, 2H).

B.(4-{4-[2-(3-Chlorophenylamino)-oxazol-5-yl]-phenyl}-cyclohexyl)-aceticacid ethyl ester

To a solution of {4-[4-(2-azidoacetyl)-phenyl]-cyclohexyl}-acetic acidethyl ester (154 mg, 0967 mmol) in 1,4-dioxane (5 mL) is addedtriphenylphosphine (122 mg, 0.967 mmol) and1-chloro-3-isothiocyanatobenzene (0.051 mL, 0.389 mmol). The reactionmixture is then heated at 90° C. for 30 min. Water (10 mL) is added andEtOAc (20 mL) is used to extract. The organic phase is washed with brine(1×15 mL), dried with MgSO₄, and concentrated to give the title compound(109 mg) as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.19 (t,J=7.20 Hz, 3H) 1.12-1.19 (m, 2H) 1.43-1.52 (m, 2H) 1.81 (d, J=10.61 Hz,4H) 1.73-1.84 (m, 1H) 2.23 (d, J=6.82 Hz, 2H) 4.07 (q, J=7.07Hz, 2H)6.99 (ddd, J=7.83, 2.02, 0.76 Hz, 1H) 7.28-7.36 (m, 3 H) 7.41 (s, 1H)7.47-7.53 (m, 3H) 7.85 (t, J=2.02 Hz, 1H) 10.52 (s, 1H); (M+H)+ 439.2.

C.(4-{4-[2-(3-Chlorophenylamino)-oxazol-5-yl]-phenyl}-cyclohexyl)-aceticacid

To a solution of(4-{4-[2-(3-Chlorophenylamino)-oxazol-5-yl]-phenyl}-cyclohexyl)-aceticacid ethyl ester (0.10 g) in 6 mL THF/water (2:1) was added 2 mL of a10% aqueous LiOH solution. The reaction mixture was then heated to 150°C. under microwave heating for 20 min. Acidification with concentratedHCl afforded a precipitate which was filtered to afford the titlecompound: ¹H NMR (400 MHz, DMSO-d6) δ ppm 1.14-1.25 (m, 2H) 1.48-1.60(m, 2H ) 1.76-1.83 (m, 1H) 1.86-1.94 (m, 4H) 2.21 (d; J=7.07 Hz, 2H)7.06 (dd, J=8.21, 1.64 Hz, 1H) 7.34-7.43 (m, 3H) (s, 1H) 7.53-7.59 (m,3H) 7.91 (t, J=2.02 Hz, 1H) 10.59 (s, 1H) 12.03 (br. s., 1H); MS(M+H)⁺=411.1.

Alternatively, the methyl ester can be dissolved in THF and treated withaqueous sodium hydroxide (4 equiv). The mixture can then be stirred at50 degrees for 12 hours, at which point water may be added and most ofthe organic solvent may be removed under reduced pressure. Addition ofacetonitrile followed by cooling may yield a precipitate which can beisolated by filtration to afford the title compound as the correspondingsodium salt.

The following compounds are prepared in analogous fashion:

MS Example Chemical Name LC rt Method (M + H)⁺ 3-2(4-{4-[2-(4-Chlorophenylamino)-oxazol-5-yl]- 1.57 A 411.2phenyl}-cyclohexyl)-acetic acid 3-3(4-{4-[2-(4-Methoxyphenylamino)-oxazol-5- 1.40 A 407.2yl]-phenyl}-cyclohexyl)-acetic acid 3-4(4-{4-[2-(2-Fluorophenylamino)-oxazol-5-yl]- 1.40 A 359.1phenyl}-cyclohexyl)-acetic acid 3-5{4-[4-(2-Phenylaminooxazol-5-yl)-phenyl]- 1.37 A 377.2cyclohexyl}-acetic acid 3-6 (4-{4-[2-(3-Fluorophenylamino)-oxazol-5-yl]-1.42 A 395.2 phenyl}-cyclohexyl)-acetic acid 3-7(4-{4-[2-(2-Chlorophenylamino)-oxazol-5-yl]- 1.51 A 410.9phenyl}-cyclohexyl)-acetic acid 3-8(4-{4-[2-(3-Cyanophenylamino)-oxazol-5-yl]- 1.34 A 402.1phenyl}-cyclohexyl)-acetic acid 3-9{4-[4-(2-Cyclohexylaminooxazol-5-yl)- 1.4 A 383.0phenyl]-cyclohexyl}-acetic acid 3-10(4-{4-[2-(3,4-Dichlorophenylamino)-oxazol- 1.58 A 445.15-yl]-phenyl}-cyclohexyl)-acetic acid 3-11(4-{4-[2-(3-Chloro-4-fluorophenylamino)- 1.50 A 429.1oxazol-5-yl]-phenyl}-cyclohexyl)-acetic acid 3-12 (4-{4-[2-(4-Chloro-3-1.61 A 479.1 trifluoromethylphenylamino)-oxazol-5-yl]-phenyl}-cyclohexyl)-acetic acid 3-13(4-{4-[2-(3,5-Difluorophenylamino)-oxazol-5- 1.48 A 412.1yl]-phenyl}-cyclohexyl)-acetic acid 3-14(4-{4-[2-(3,5-Dichlorophenylamino)-oxazol- 1.61 A 445.05-yl]-phenyl}-cyclohexyl)-acetic acid 3-15 (4-{4-[2-(2-Chloro-4- 1.62 A479.0 trifluoromethylphenylamino)-oxazol-5-yl]-phenyl}-cyclohexyl)-acetic acid 3-16(4-{4-[2-(2-Trifluoromethylphenylamino)- 1.50 A 445.2oxazol-5-yl]-phenyl}-cyclohexyl)-acetic acid 3-17(4-{4-[2-(3-Fluoro-4-methylphenylamino)- 1.44 A 409.2oxazol-5-yl]-phenyl}-cyclohexyl)-acetic acid 3-18{4-[4-(2-p-Tolylaminooxazol-5-yl)-phenyl]- 1.40 A 391.2cyclohexyl}-acetic acid 3-19 (4-{4-[2-(3-Chloro-4-methylphenylamino)-1.54 A 425.1 oxazol-5-yl]-phenyl}-cyclohexyl)-acetic acid

Example 3-204-(4-{4-[2-(3-Chlorophenylamino)-oxazol-5-yl]-phenyl}-cyclohexyl)-butyricacid

A.(4-{4-[2-(3-Chlorophenylamino)-oxazol-5-yl]-phenyl}-cyclohexyl)-acetaldehyde

To a solution of(4-{4-[2-(3-Chlorophenylamino)-oxazol-5-yl]-phenyl}-cyclohexyl)-aceticacid ethyl ester (500 mg, 1.14 mmol) in DCM (20 mL) at −78° C. is addedDIBAL-H (1 M in toluene, 2.14 mL, 2.14 mmol) and the mixture is allowedto stir at −78° C. for 2 h. Methanol (3 mL) is added to quench thereaction. The reaction mixture is then poured in ice and Rochelle's salt(4 g). Water (20 mL) is added and the mixture is extracted with EtOAc(3×30 mL). The organic phase is washed with brine (3×30 mL), dried withNa₂SO₄ and concentrated to give the title compound (253 mg) as a whitesolid: (M+H)+ 395.2.

B.(E)-4-(4-{4-[2-(3-Chlorophenylamino)-oxazol-5-yl]-phenyl}-cyclohexyl)-but-2-enoicacid benzyl ester

To a mixture of (benzyloxycarbonylmethyl)-triphenylphosphionium bromide(315 mg, 0.642 mmol) in THF (6 mL) at 0° C. is added NaH (60% in mineraloil, 27 mg, 0.642 mmol) and the suspension is allowed to stir at 0° C.for 30 min.(4-{4-[2-(3-Chlorophenylamino)-oxazol-5-yl]-phenyl}-cyclohexylyacetaldehyde(253 mg, 0.642 mmol) in THF (4 mL) is added dropwise. The reactionmixture is then stirred a 0° C. for 30 min and the at ambienttemperature for 18 h. Water (10 mL) and HCl solution (1N, 15 mL) isadded, and the reaction mixture is extracted with EtOAc (3×15 mL). Theorganic phase is washed with water (1×15 mL), brine (3×20 mL), dried andconcentrated to give the title compound (279 mg) as an off-white solid:1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.02-1.14 (m, 2H) 1.34-1.49 (m, 3H)1.59-1.73 (m, 1H) 1.80-1.87 (m, 3H) 2.11 (t, J=8.00 Hz, 2H) 2.46 (ddd,J=11.68, 9.16, 2.91 Hz, 1H) 5.11 (s, 2H) 5.82 (d, J=15.66 Hz, 1H)6.90-6.99 (m, 1H) 7.14-7.17 (d, 8.08 Hz, 2H) 7.24-7.28 (m, 3H) 7.28-7.32(m, 6H) 7.40 (d, J=8.08 Hz, 1H) 7.49 (s, 1H); (M+H)+ 527.2.

C.4-(4-{4-[2-(3-Chlorophenylamino)-oxazol-5-yl]-phenyl}-cyclohexyl)-butyricacid

To a solution of(E)-4-(4-{4-[2-(3-chlorophenylamino)-oxazol-5-yl]-phenyl}-cyclohexyl)-but-2-enoicacid benzyl ester (139 mg, 0.283 mmol) in EtOAc/EtOH (5:1 v/v, 6 mL) isadded Pd(OH)₂ (100 mg) the mixture is stirred in an hydrogenated at 1atm for 72 h. The catalyst is filtered and washed with EtOAc. Thefiltrated is then concentrated and dried under high vacuum to give thetitle compound (107 mg) as a white solid: 1H NMR (400 MHz, DMSO-d6) δppm 0.98-1.09 (m, 2H) 1.18-1.25 (m, 2H) 1.39-1.48 (m, 2H) 1.49-1.57 (m,2 H) 1.82 (d, J=10.11 Hz, 4H) 1.74-1.85 (m, 1H) 2.18 (t, J=7.33 Hz, 2H)6.99 (ddd, J=7.96, 2.02, 0.88 Hz, 1H) 7.28-7.33 (m, 3H) 7.40 (s, 1H)7.47-7.52 (m, 3H) 7.85 (t, J=2.02 Hz, 1H); (M+H)⁺=439.0.

Example 3-21(E)-4-(4-{4-[2-(3-Chlorophenylamino)-oxazol-5-yl]-phenyl}-cyclohexyl)-but-2-enoicacid

To a solution of(E)-4-(4-{4-[2-(3-chlorophenylamino)-oxazol-5-yl]-phenyl}-cyclohexyl)-but-2-enoicacid benzyl ester (139 mg, 0.283 mmol) in 3 mL of THF/water (2:1) wasadded 1 mL of 10% aqueous LiOH. The homogeneous reaction was allowed tostir at 50° C. overnight. Acidification with concentrated HCl afforded aprecipitate which was filtered and then purified by reverse-phasepreparative HPLC to afford the title compound: 1H NMR (400 MHz, DMSO-d6)δ ppm 0.98-1.09 (m, 2H) 1.41 (td, J=11.62, 3.28 Hz, 3H) 1.71-1.78 (m,4H) 2.07 (t, J=6.82 Hz, 2H) 5.72 (d, J=15.41 Hz, 1H) 6.76 (ddd, J=15.47,7.64, 7.45 Hz, 1H) 6.92 (ddd, J=7.89, 1.96, 0.76 Hz, 1H) 7.21-7.28 (m,2H) 7.23 (d, J=8.34 Hz, 1H) 7.34 (s, 1H) 7.41-7.45 (m, 3 H) 7.78 (t,J=2.02 Hz, 1H) 10.47 (br. s., 1H); (M+H)+ 437.2.

Example 3-223-[2-(4-{4-[2-(3-Chlorophenylamino)-oxazol-5-yl]-phenyl}-cyclohexyl)-acetylamino]-propionicacid

A.3-[2-(4-{4(2-(3-Chlorophenylamino)-oxazol-5-yl]-phenyl}-cyclohexyl)-acetylamino]-propionicacid ethyl ester

To a solution of 3-aminopropionic acid ethyl ester (41 mg, 0.268 mmol)and Et3N (0.082 mL, 0.730 mmol) is added a solution of(4-{4-[2-(3-Chlorophenylamino)-oxazol-5-yl]-phenyl}-cyclohexyl)-aceticacid (100 mg, 0.243 mmol) in DMF (4 mL), HATU (102 mg, 0.268 mmol) andiPr₂NEt (0.127 mL, 0.73 mmol). The reaction mixture is allowed to stirat ambient temperature for 18 h. Water is added and EtOAc is used toextract. The organic layer is washed with brine, dried with Na₂SO₄ andconcentrated to give the title compound (140 mg) as a tan solid: 1H NMR(400 MHz, DMSO-d6) δ ppm 1.02-1.13 (m, 2H) 1.18 (t, J=7.07Hz, 3H)1.38-1.50 (m, 2H) 1.71 (dd, J=7.71, 4.17 Hz, 1H) 1.78 (t, J=12.63Hz, 4H)1.98 (d, J=6.57 Hz, 2H) 2.44 (t, J=6.82 Hz, 2H) 3.25-3.28 (m, 2H) 4.06(q, J=7.07 Hz; 2H) 6.99 (ddd, J=7.89, 1.96, 1.01 Hz, 1H) 7.27-7.35 (m,1H) 7.29 (d, J=8.59 Hz, 2H) 7.40 (s, 1H) 7.50 (d, J=8.34 Hz, 1H)7.47-7.52 (m, 1H) 7.85 (t, J=2.02 Hz, 1H) 7.88 (t, J=5.81 Hz, 1H) 10.52(s, 1H); (M+H)+ 510.2.

B.3-[2-(4-{4-[2-(3-Chlorophenylamino)-oxazol-5-yl]-phenyl}-cyclohexyl)-acetylamino]-propionicacid

The title compound is prepared in analogous fashion to the proceduresdescribed above: 1H NMR (400 MHz, DMSO-d6) δ ppm 0.98-1.10 (m, 2H)1.35-1.46 (m, 2H) 1.63-1.70 (m, 1H) 1.71-1.79 (m, 4H) 1.95 (d, J=6.82Hz, 2H) 2.30 (t,J=6.95 Hz, 2H) 2.38-2.44 (m, 1H) 3.20 (d, J=19.45 Hz,1H) 3.20 (d, J=5.81 Hz, 1H) 6.96 (ddd, J=7.96, 2.02, 0.88 Hz, 1H) 7.27(dd, J=9.85, 8.34 Hz, 3H) 7.38 (s, 1 H) 7.44-7.49 (m, 3H) 7.82 (t,J=2.02 Hz, 2H) (M+H)⁺=482.2.

Example 3-23{[2-(4-{4-[2-(3-Chlorophenylamino)-oxazol-5-yl]-phenyl}-cyclohexyl)-acetyl]-methyl-amino}-aceticacid

The title compound is prepared in analogous fashion to Example 3-22using methylamino-acetic acid ethyl ester 1H NMR (400 MHz, DMSO-d6) δppm 0.90-0.99 (m, 2H), 1.24-1.36 (m, 2H), 1.60-1.70 (m, 5H), 1.96 and2.11 (d rotamers, J=6.57 Hz and 6.82 Hz, 2H), 2.64 and 2.86 (s rotamers,3H), 3.78 and 3.80 (br.s. and s rotamers, 2H), 6.84 (dt, J=7.83, 1.01Hz, 1H), 7.12-7.20 (m, 3 H), 7.26 (d, J=1.52 Hz, 1H), 7.32-7.37 (m, 3H),7.70 (t, J=2.02 Hz, 1H), 10.40 (br. s., 1H); (M+H)+=482.2.

Example 3-24{4′-[2-(3-Chlorophenylamino)-oxazol-5-yl]-biphenyl-4-yl}-acetic acid

The title compound is prepared analogously to Example 3-1 using2-bromo-1-(4-bromophenyl)-ethanone and[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid asstarting materials: ¹H NMR (400 MHz, DMSO-d6) δ ppm 3.80 (s, 2H) 7.19(d, J=7.83 Hz, 1H) 7.50-7.58 (m, 3H) 7.72-7.76 (m, 2H) 7.83-7.90 (m, 4H)7.95 (m, 2H) 8.05 (t, J=2.15 Hz, 1H) 10.78 (s, 1H) 12.51 (br. s., 1 H);(M+H)⁺=405.1.

The following compounds are prepared in similar fashion:

MS Example Chemical Name LC rt Method (M + H)⁺ 3-253-{4′-[2-(3-Chlorophenylamino)-oxazol-5-yl]- 0.84 B 419.0biphenyl-4-yl}-propionic acid 3-264-{4′-[2-(3-Chlorophenylamino)-oxazol-5-yl]- 1.02 B 475.0biphenyl-4-yl}-2,2-dimethyl-4-oxo-butyric acid 3-274-{4′-[2-(3-Chlorophenylamino)-oxazol-5-yl]- 1.36 A 445.0biphenyl-4-yl}-4-oxo-butyric acid 3-284-{4′-[2-(3-Chlorophenylamino)-oxazol-5-yl]- 1.13 C 501.1biphenyl-4-carbonyl}-cyclohexanecarboxylic acid

Example 3-29(4-{4-[2-(3-Chlorophenylamino)-oxazol-5-yl]-phenyl}-3,6-dihydro-2H-pyridin-1-yl)-oxo-aceticacid

A.4-{4-[2-(3-Chlorophenylamino)-oxazol-5-yl]-phenyl}-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester

Preparation of -(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester has been described [Tet. Lett. 41(19), 3705-3708,2000]. The boronate ester (1.1 g, 3.6 mmol, 1.5 equiv) and[5-(4-bromo-phenyl)-oxazol-2-yl]-(3-chloro-phenyl)-amine (0.84 g, 2.4mmol, 1.0 equiv) were dissolved in 12 mL DME and then charged with 3 mLof a 2M Na₂CO₃ solution. Pd(Ph₃)₄ on polystyrene resin (0.72 g, 0.072mmol) was added, and the suspension was sparged with nitrogen for 10min, then heated to 100° C. overnight. The reaction was then filtered toremove catalyst, and following solvent removal the product wastriturated with hexanes and ether to afford the title compound: (M+H)+452.1.

B.(3-Chlorophenyl)-{5-[4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-oxazol-2-yl}-amine

To a solution of4-{4-[2-(3-chlorophenylamino)-oxazol-5-yl]-phenyl}-3,6-dihydro-2H-pyridine-1-calboxylicacid tert-butyl ester (2.5 g, 5.5 mmol) in MeOH (1 mL) is added 4M HClin dioxane (3 mL) and the mixture is stirred at RT for 2 h. It isconcentrated and used in the next step as the bis HCl salt: (M+H)+352.1.

C.(4-{4-[2-(3-Chlorophenylamino)-oxazol-5-yl]-phenyl}-3,6-dihydro-2H-pyridin-1-yl)-oxo-aceticacid ethyl ester

To a solution of(3-chlorophenyl)-{5-[4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-oxazol-2-yl}-aminebis HCl salt (50 mg, 0.12 mmol) in DCM (1 mL) at 0° C. is added DIEA(0.052 mL, 0.3 mmol) and after stirring for 5 min, ethylchlorooxoacatate (0.016 mL, 0.14 mmol) is added dropwise. The mixture isstirred for 2 h and the mixture is purified by RP-HPLC to give the titlecompound: ¹H NMR (400 MHz, DMSO-d6) δ 1.30 (q, J=7.07 Hz, 3H) 2.58 (m,2H) 3.55-3.90 (m, 2H) 4.07-4.20 (m, 1H) 4.32 (m, 2H) 6.21-6.29 (m, 1H)7.00 (dd, J=7.45, 1.64 Hz, 1H) 7.34 (t, J=8.08 Hz, 1H) 7.47-7.60 (m, 6H)7.86 (t, J=2.02 Hz, 1H); (M+H)+ 452.1.

D.(4-{4-[2-(3-Chlorophenylamino)-oxazol-5-yl]-phenyl}-3,6-dihydro-2H-pyridin-1-yl)-oxo-aceticacid

Using the saponification procedures described above, the title compoundis obtained: ¹H NMR (400 MHz, DMSO-d6) δ 3.37 (br. s., 2H) 3.64 (d,J=15.92 Hz, 2H) 4.08 (br.s., 2H) 6.30 (br. s, 1H) 7.05 (dd, J=7.83, 2.02Hz, 1H) 7.39 (t, J=8.08 Hz, 1H) 7.53-7.60 (m, 4H) 7.60-7.64 (m, 2H) 7.92(t, J=1.89 Hz, 1H) 10.73 (d, J=4.04 Hz, 1H); (M+H)⁺=424.1.

Example 3-304-{4-[2-(3-Chloro-phenylamino)-oxazol-5-yl]-phenyl}-3,6-dihydro-2H-pyridine-1-sulfonicacid amide

The title compound is prepared from(3-chlorophenyl)-{5-[4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-oxazol-2-yl}-aminebis HCl salt in analogous fashion using N-Boc chlorosulfonamide followedby TFA-mediated deprotection: ¹H NMR (400 MHz, DMSO-d6) 2.55 (br. s., 2H) 3.15 (t, J=5.56 Hz, 2H) 3.65 (d, J=2.78 Hz, 2H) 6.22 (t, J=3.28 Hz,1H) 6.92 (dd, J=7.83, 1.52 Hz, 1H) 7.26 (t, J=8.08 Hz, 1H) 7.39-7.53 (m,7H) 7.79 (t, J=2.02 Hz, 1H); (M+H)+ 431.1.

Using the appropriate acylating agent, the following compounds may alsobe prepared:

MS Example Chemical Name LC rt Method (M + H)⁺ 3-314-{4-[2-(3-Chloro-phenylamino)-oxazol-5-yl]- 1.55 A 531.2phenyl}-3,6-dihydro-2H-pyridine-1-sulfonic acid amide-N-carboxylic acidtert-butyl ester 3-32 4-(4-{4-[2-(3-Chloro-phenylamino)-oxazol-5- 1.37 A480.0 yl]-phenyl}-3,6-dihydro-2H-pyridin-1-yl)-2,2-dimethyl-4-oxo-butyric acid 3-334-(4-{4-[2-(3-Chloro-phenylamino)-oxazol-5- 1.19 A 452.0yl]-phenyl}-3,6-dihydro-2H-pyridin-1-yl)-4- oxo-butyric acid 3-342-(4-{4-[2-(3-Chloro-phenylamino)-oxazol-5- 1.23 A 500.1yl]-phenyl}-3,6-dihydro-2H-pyridine-1- carbonyl)-benzoic acid

Example 3-35(1R,2R)-2-{4′-[2-(3-Chlorophenylamino)-oxazol-5-yl]-biphenyl-4-carbonyl}-cyclohexanecarboxylicacid

A.(3-Chloro-phenyl)-{5[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]oxazol-2-yl}-amine

The title compound is prepared from[5-(4-bromophenyl)-oxazol-2-yl]-(3-chlorophenyl)-amine usingbis(pinacolato)diboron, KOAc, and PdCl₂dppf CH₂Cl₂in DME at 120° C. for20 min under microwave heating. The reaction mixture is then useddirectly in the next step: (M+H)+ 397.1.

B.(1R,2R)-2-{4′-[2-(3-Chlorophenylamino)-oxazol-5-yl]-biphenyl-4-carbonyl}-cyclohexanecarboxylicacid

Using (1R,2R)-2-(4-Bromo-benzoyl)-cyclohexanecarboxylic acid, the titlecompound may be prepared: ¹H NMR (400 MHz, DMSO-d6) δ 1.16-1.28 (m, 1H)1.36-1.58 (m, 3H) 1.77-1.91 (m, 2H) 2.01 (d, J=10.61 Hz, 1H) 2.17 (dd,J=12.25, 2.91 Hz, 1H) 2.75 (dd, J=11.75, 2.91 Hz, 1H) 3.66-3.75 (m, 1H)7.08 (dd, J=7.83, 1.26 Hz, 1H) 7.42 (t, J=8.08 Hz, 1H) 7.59 (dd, J=8.34,1.26 Hz, 1H) 7.68 (s, 1H) 7.79 (d, J=8.34 Hz, 2H) 7.94 (t, J=8.59 Hz,5H) 8.15 (d, J=8.59 Hz, 2H) 10.70 (br. s., 1H); (M+H)⁺=501.0.

The following compounds are prepared in analogous fashion:

MS Example Chemical Name LC rt Method (M + H)⁺ Ex. 3-36(trans)-2-{4′-[2-(3-Chlorophenylamino)- 1.1 B 501.1oxazol-5-yl]-biphenyl-4-carbonyl}- cyclohexanecarboxylic acid Ex. 3-37(trans)-2-{4′-[2-(3-Chlorophenylamino)- 1.52 A 487.0oxazol-5-yl]-biphenyl-4-carbonyl}- cyclopentanecarboxylic acid Ex-3-38(4-{4′-[2-(3-Chloro-phenylamino)-oxazol-5- 1.22 B 487.1yl]-biphenyl-4-yl}-cyclohexyl)-acetic acid

Example 4-1(4-{5-[6-(6-Trifluoromethyl-pyridin-3-ylamino)-pyridin-3-yl]-spirocyclohexylidenyl-1,1′-indanyl}-aceticacid

A.{4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)]-spirocyclohexylidenyl-1,1′-indanyl}aceticacid methyl ester

To a solution of (5-bromo-spirocyclohexylidenyl-1,1′-indanyl)-aceticacid methyl ester (reported in WO2004 047755, 6.9 g, 20.7 mmol, 1.0equiv) in 35 mL dimethoxyethane was added bis(pinacolato)diboron (6.4 g,24.8 mmol, 1.2 equiv), potassium acetate (5.0 g, 51.8 mmol, 2.5 equiv)and PdCl₂dppf(dichloromethane) complex (0.67 g, 0.83 mmol, 0.04 equiv).The reaction mixture was sparged with nitrogen for 10 minutes, thensealed and heated to 100° C. for 18 h. The reaction was cooled to roomtemperature, filtered, and concentrated in vacuo. Purification by flashchromatography (5-15% EtOAc in hexanes) afforded the title compound as awhite solid:

¹H NMR (400 MHz, CDCl₃) δ 1.26 (s, 12H) 1.65-1.78 (m, 4H) 2.00-2.15 (m,3H) 2.25 (m, 1H) 2.33 (m, 1H) 2.87 (t, J=7.33 Hz, 2H) 3.63 (s, 3H) 3.74(m, 1H) 5.63 (s, 1H) 7.07 (d, J=7.58 Hz, 1H) 7.58 (dd, J=7.58, 0.76 Hz,1H) 7.62 (s, 1H); (M+H)+ 383.2.

B. (5-Bromo-pyridin-2-yl)-(6-trifluoromethyl-pyridin-3-yl)-amine

A mixture of 5-amino-2-(trifluoromethyl)pyridine (0.5 g, 3.0 mmol, 1.0equiv) and 5-bromo-2-fluoropyridine (0.47 mL, 4.6 mmol, 1.5 equiv) in 2mL 1-butanol was charged with 0.15 mL of 4.0 M HCl (in dioxane) andheated to 150° C. via microwave heating. After cooling to roomtemperature, the reaction mixture was partitioned between ethyl acetateand saturated bicarbonate, and the organic extracts were washed withbrine and dried over sodium sulphate. Purification of the crude productby flash chromatography afforded the title compound: ¹H NMR (400 MHz,CDCl₃) δ 6.63 (br. s., 1H) 6.67 (d, J=9.35 Hz, 1H) 7.56 (d, J=8.59 Hz,1H) 7.62 (dd, J=8.84, 2.53 Hz, 1H) 8.22-8.66 (m, 2H) 8.57 (d, J=2.78 Hz,1H); (M+H)+ 320.0.

C.(4-{5-[6-(6-Trifluoromethyl-pyridin-3-ylamino)-pyridin-3-yl]-spirocyclohexylidenyl-1,1’-indanyl}-aceticacid methyl ester

A microwave vial was charged with5-Bromo-pyridin-2-yl)-(6-trifluoromethyl-pyridin-3-yl)-amine (0.23 g,0.71 mmol, 1.0 equiv) and{4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)]-spirocyclohexylidenyl-1,1′-indanyl}-aceticacid methyl ester (0.30 g, 0.78 mmol, 1.0 equiv) in 4 mLdimethoxyethane. To this solution was added 2M Na2CO3 (0.89 mL, 2.5equiv) followed by PdCl₂dppf(dichloromethane) complex (0.023 g, 0.028mmol, 0.04 equiv). The mixture was sparged with nitrogen for 5 minutesand then heated to 150° C. for 30 min. The reaction was partitionedbetween EtOAc and water, and the organic extracts were washed with brineand dried over magnesium sulphate. Purification of the crude product byflash chromatography afforded the title compound: ¹H NMR (400 MHz,CDCl₃) δ 1.69-1.80 (m, 4H) 2.07-2.19 (m, 3H) 2.24-2.32 (m, 1H) 2.37 (m,1H) 2.94 (t, J=7.33 Hz, 2H) 3.65 (s, 3H) 3.77 (m, 1H) 5.66 (s, 1H) 6.84(d, J=8.59 Hz, 1H) 6.90 (br. s., 1H) 7.13 (d, J=7.83 Hz, 1H) 7.29 (dd,J=7.96; 1.64 Hz, 1H) 7.33 (s, 1H) 7.57 (d, J⁻43.59 Hz, 1H) 7.75 (dd,J=8.59, 2.53 Hz, 1H) 8.29 (dd, J=8.72, 2.15 Hz, 1H) 8.42 (d, J=2.02 Hz,1H) 8.60 (d, J=2.53 Hz, 1H); (M+H)+ 494.2.

D.(4-{5-[6-(6-Trifluoromethyl-pyridin-3-ylamino)-pyridin-3-yl]-spirocyclohexylidenyl-1,1′-indanyl}-aceticacid

(4-{5-[5-(6-Trifluoromethyl-pyridin-3-ylamino)-pyridin-2-yl]-spirocyclohexylidenyl-1,1′-indanyl}-aceticacid methyl ester (0.36 g, 0.73 mmol, 1.0 equiv) was dissolved in 3 mLTHF/MeOH (2:1) and charged with 1 mL 10% aqueous LiOH. The reaction wasstirred at 60° C. for 3 hours. The volatile organics were removed, andthen the pH was adjusted to pH 1 using a few drops of concentrated HCl.The resulting precipitate was filtered and dried overnight to afford thetitle compound: ¹H NMR (400 MHz, DMSO-d6) δ 1.56-1.71 (m, 4H) 2.08 (dd,J=14.91, 1.77 Hz, 2H) 2.07 (s, 1H) 2.26 (dd, J=3.54, 1.77 Hz, 1H) 2.34(dd, J=13.14, 8.84 Hz, 1H) 2.88 (t, J=7.33 Hz, 2H) 3.68 (d, J=13.89 Hz,1H) 5.60 (s, 1H) 6.95 (d, J=8.84 Hz, 1H) 7.20 (d, J=7.83 Hz, 1H) 7.36(d, J=7.83 Hz, 1H) 7.42 (s, 1H) 7.72 (d, J=8.84 Hz, 1H) 7.89 (dd,J=8.84, 2.53 Hz, 1H) 8.46 (d, J=2.53 Hz, 1H) 8.50 (dd, J=8.84, 2.27 Hz,1H) 8.84 (d, J=2.53 Hz, 1H) 9.79 (s, 1H); (M+H)+ 480.2.

Alternatively, the methyl ester can be dissolved in THF and treated withaqueous sodium hydroxide (4 equiv). The mixture can then be stirred at50 degrees for 12 hours, at which point water may be added and most ofthe organic solvent may be removed under reduced pressure. Addition ofacetonitrile followed by cooling may yield a precipitate which can beisolated by filtration to afford the title compound as the correspondingsodium salt.

Example 4-2(4-{5-[6-(6-Trifluoromethyl-pyridin-3-ylamino)-pyridin-3-yl]-spirocyclohexyl-1,1′-indanyl}-aceticacid

To a solution of(4-{5-[5-(6-Trifluoromethyl-pyridin-3-ylamino)-pyridin-2-yl]-spirocyclohexylidenyl-1,1′-indanyl}-aceticacid (0.15 g, 0.31 mmol, 1.0 equiv) in 5 mL EtOH was added 20 mgplatinum oxide. The reaction vessel was then purged with hydrogen, andthen stirred under balloon pressure overnight. The reaction was filteredthrough Celite and concentrated in vacuo. Purification by reverse-phaseHPLC afforded two separable diastereomers (cis and trans):

Diastereomer 1: ¹H NMR (400 MHz, DMSO-d6) δ 1.27 (m, 2H) 1.55-1.63 (m,2H) 1.67-1.81 (m, 4H) 1.84 (br. s., 1H) 2.03 (t, J=7.33 Hz, 2H) 2.24 (d,J=6.82 Hz, 2H) 2.95 (t, J=7.45 Hz, 2H) 7.09 (d, J=8.59 Hz, 1H) 7.33 (d,J=7.83 Hz, 1H) 7.53 (s, 1H) 7.51 (d, J=7.83 Hz, 1H) 7.86 (d, J=8.84 Hz,1H) 8.03 (dd, J=8.59, 2.53 Hz, 1H) 8.60 (d, J=2.02 Hz, 1H) 8.64 (dd,J=8.46, 2.15 Hz, 1H) 8.98 (d, J=2.53 Hz, 1H) 9.91 (s, 1H)

Diastereomer 2: ¹H NMR (400 MHz, DMSO-d6) δ 1.20 (m, 2H) 1.25-1.35 (m,2H) 1.43-1.57 (m, 4H) 1.72 (t, J=7.33 Hz, 2H) 1.80 (br. s., 1H) 2.17 (d,J=7.33 Hz, 2H) 2.66 (t, J=7.07 Hz, 2H) 6.80 (d, J=8.84 Hz, 1H) 7.24 (d,J=7.58 Hz, 2H) 7.19-7.26 (m, 1H) 7.57 (br. s., 1H) 7.75 (dd, J=8.59,2.53 Hz, 1H) 8.31 (d, J=2.27 Hz, 1H) 8.35 (dd, J=8.84, 2.53 Hz, 1H) 8.69(d, J=2.53 Hz, 1H) 9.63 (s, 1H); (M+H)+ 482.2.

Example 4-3(4-{4-[6-(3-Chloro-phenylamino)-pyridin-3-yl]-phenyl}-cyclohexyl)-aceticacid

A. (5-Bromo-pyridin-2-yl)-(3-chlorophenyl)-amine

A 1-dram vial was charged with 2,5-dibromopyridine (0.5 g, 2.1 mmol, 1.0equiv) and 3-chlorophenyl amine (0.89 mL, 8.4 mmol. 4 equiv). The neatreaction mixture was heated to 180° C. for 3 hours. The reaction wascooled, then purified by flash chromatography to afford the titlecompound. (M+H)+ 285.0.

B.(4-{4-[6-(3-Chloro-phenylamino)-pyridin-3-yl]-phenyl}-cyclohexyl)-aceticacid

The title compound was synthesized using{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclohexyl}-aceticacid methyl ester and the procedures described above: ¹H NMR (400 MHz,DMSO-d6) δ 1.30-1.36 (m, 1H) 1.65-1.78 (m, 1H) 1.85 (m, 5H) 1.89-1.97(m, 1H) 2.00-2.11 (m, 1H) 2.53 (d, J=7.58 Hz, 2H) 2.80 (d, J=9.60 Hz,1H) 7.16 (t, J=8.21 Hz, 2H) 7.57 (d, J=8.34 Hz, 2H) 7.52 (t, J=8.08 Hz,2H) 7.81 (d, J=8.08 Hz, 2H) 7.74-7.83 (m, 1H) 8.15 (dd, J=8.59, 2.53 Hz,1H) 8.31 (t, J=2.02 Hz, 1H) 8.76 (d, J=2.78 Hz, 1H) 9.65 (s, 1H); (M+H)+421.2.

The following compounds may be prepared in analogous fashion using andthe appropriate aniline:

MS Example Chemical Name LC rt Method (M + H)⁺ Ex. 4-4(4-{4-[6-(3-methylphenylamino)-pyridin-3- 1.53 A 401.2yl]-phenyl}-cyclohexyl)-acetic acid Ex. 4-5(4-{4-[6-(3-Trifluoromethylphenylamino)- 1.62 A 455.2pyridin-3-yl]-phenyl}-cyclohexyl)-acetic acid Ex. 4-6(4-{4-[6-(3-Methoxyphenylamino)-pyridin-3- 1.55 A 417.2yl]-phenyl}-cyclohexyl)-acetic acid Ex. 4-7(4-{4-[6-(2-Fluorophenylamino)-pyridin-3-yl]- 1.49 A 405.2phenyl}-cyclohexyl)-acetic acid Ex. 4-8(4-{4-[6-(2-Methoxyphenylamino)-pyridin-3- 1.55 A 417.2yl]-phenyl}-cyclohexyl)-acetic acid Ex. 4-9(4-{4-[6-(6-Trifluoromethyl-pyridin-3- 1.53 A 456.3ylamino)-pyridin-3-yl]-phenyl}-cyclohexyl)- acetic acid

The following compounds may also be prepared in similar fashion from thecorresponding aniline and haloarene:

Example Name LC rt Method (M + H)+ Ex. 4-10 (4-{4-[6-(6-Methoxy- 1.47 A432.1 pyridin-3-ylamino)-5- methyl-pyridin-3-yl]- phenyl}-cyclohexyl)-acetic acid Ex. 4-11 (4-{4-[5-Fluoro- 1.44 A 436.16-(6-methoxy-pyridin-3- ylamino)-pyridin-3-yl]- phenyl}-cyclohexyl)-acetic acid

p Example 4-12(4-{4-[6-(2-Methyl-6-trifluoromethyl-pyridin-3-ylamino)-pyridin-3-yl]-phenyl}-cyclohexyl)-aceticacid

A.(5-Bromo-pyridin-2-yl)-(2-methyl-6-trifluoromethyl-pyridin-3-yl)-amine

2,5-dibromopyridine (474 mg, 2 mmol) and2-Methyl-6-trifluoromethyl-pyridin-3-ylamine (352 g, 2 mmol) weredissolved in 1,4-dioxane (4 mL) in a pressure vessel. Pd₂dba₃ (55 mg,0.06 mmol) and XANTPHOS (46 mg, 0.08 mmol) were added, followed bycesium carbonate (1.3 g, 4 mmol). The mixture was sparged with nitrogenfor 10 minutes, then the vessel was sealed and heated at 100° C. for 18hours. The mixture was partitioned between EtOAc and saturated aqueousNH₄Cl, then the organic layer was washed with brine, dried withmagnesium sulfate, filtered, and concentrated via rotary evaporation.The crude material was purified via column chromatography on silica gel,eluting with a gradient of EtOAc/hexanes (7-60%) to obtain the targetcompound as a solid: ¹H NMR (400 MHz, CDCl₃) δ ppm 2.62 (s, 3H) 6.36(br. s., 1H) 6.75 (d, J=8.59 Hz, 1H) 7.53 (d, J=8.34 Hz, 1H) 7.69 (dd,J=8.84, 2.53 Hz, 1H) 8.32-8.37 (m, 2H); MS (M+H)+ 334.7.

B.(4-{4-[6-(2-Methyl-6-trifluoromethyl-pyridin-3-ylamino)-pyridin-3-yl]-phenyl}-cyclohexyl)-aceticacid methyl ester

(5-Bromo-pyridin-2-yl)-(2-methyl-6-trifluoromethyl-pyridin-3-yl)-amine(290 mg, 0.87 mmol) and{4-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclohexyl}-aceticacid methyl ester (312 mg, 0.87 mmol) were dissolved in anhydrous DME (3mL) in a pressure vessel. PdCl₂dppf (21 mg, 0.026 mmol) was added,followed by aqueous sodium carbonate (2M, 0.870 mL, 1.74 mmol). Themixture was sparged with nitrogen for 10 minutes, then the vessel wassealed and heated at 80° C. for 18 hours. The mixture was partitionedbetween EtOAc and water, washed with brine, dried with magnesiumsulfate, filtered, and concentrated via rotary evaporation. The crudematerial was purified via column chromatography on silica gel, elutingwith a gradient of EtOAc/hexanes (7-50%) to obtain the target compoundas a solid: ¹H NMR (400 MHz, DMSO-d6) δ ppm 1.08-1.21 (m, 2H) 1.50 (td,J=12.44, 10.23 Hz, 2H) 1.81 (m, 4H) 2.25 (d, J=6.57 Hz, 2H) 2.59 (s, 3H)3.60 (s, 3H) 7.22 (d, J=8.59 Hz, 1H) 7.31 (d, J=8.34 Hz, 2H) 7.57 (d,J=8.34 Hz, 2H) 7.66 (d, J=8.59 Hz, 1H) 7.97 (dd, J=8.59, 2.53 Hz, 1H)8.48 (d, J=2.53 Hz, 1H) 8.64 (s, 1H) 8.66 (d, J=8.34 Hz, 1H); MS (M+H)+484.3.

C.(4-{4-[6-(2-Methyl-6-trifluoromethyl-pyridin-3-ylamino)-pyridin-3-yl]-phenyl}-cyclohexyl)-aceticacid

(4-{4-[6-(2-Methyl-6-trifluoromethyl-pyridin-3-ylamino)-pyridin-3-yl]-phenyl}-cyclohexyl)-aceticacid methyl ester (332 g, 0.69 mmol) was dissolved in THF/MeOH (3:1, 4mL) and to it was added aqueous LiOH (4M, 1 mL). The mixture was stirredat room temperature for 18 hours, then the organic solvent was removedvia rotary evaporation. The remaining crude was diluted with water andthe pH was adjusted to 2 with 1M HCl. The resulting precipitate wascollected by filtration and dried under vacuum to obtain the titlecompound as a white solid: ¹H NMR (400 MHz, DMSO-d6) δ ppm 0.95-1.04 (m,2H) 1.44 (dd, J=12.51, 2.91Hz, 2H) 1.67 (br. s., 1H) 1.74-1.87 (m, 6H)2.47 (m, 1H) 2.60 (s, 3H) 7.25 (d, J=8.59 Hz, 1H) 7.30 (d, J=8.34 Hz,2H) 7.56 (d, J=8.34 Hz, 2H) 7.66 (d, J=8.34 Hz, 1H) 7.97 (dd, J=8.72,2.65 Hz, 1H) 8.48 (d, J=2.27 Hz, 1H) 8.67 (d, J=8.34 Hz, 1H) 8.80 (s,1H); MS (M+H)+ 470.3.

Example 4-13Oxo-(4-{4-[6-(6-trifluoromethyl-pyridin-3-ylamino)-pyridin-3-yl]-phenyl}-piperidin-1-yl)-aceticacid

A. 4-(4-Bromo-phenyl)-piperidine-1-carboxylic acid tert-butyl ester

To a solution of 4-(4-Bromo-phenyl)-piperidine (1 g, 4.2 mmol) in DMF (8mL) was added NaH (168 mg, 4.2 mmol, 60% in mineral oil). The slurry wasstirred for 15 minutes, then di-butyl dicarbonate (915 mg, 4.2 mmol) wasadded. The mixture was stirred for 18 hours, then quenched withmethanol, and partitioned between 30% EtOAc/hexanes and water. Theorganic layer was dried with magnesium sulfate, filtered, andconcentrated via rotary evaporation to yield the title compound as awhite solid, which was taken on to the next step without furtherpurification; ¹H NMR (400 MHz, CDCl₃-d) δ ppm 1.49 (s, 9H) 1.58 (qd,J=12.67, 4.42 Hz, 2H) 1.80 (d,J=13.14 Hz, 2H) 2.61 (tt, J=12.22, 3.57Hz, 1H) 2.79 (t, J=12.63 Hz, 2H) 4.24 (d, J=6.57 Hz, 2H) 7.08 (m, 2H)7.43 (m, 2H); MS (M+H)+ 340.8 and 342.8.

B.4-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]piperidine-1-carboxylicacid tert-butyl ester

4-(4-Bromo-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (1.4 g,4.1 mmol) and bispinacolatodiboron (1.15 g, 4.53 mmol) were dissolved inDME (3 mL) in a pressure vessel, and to the solution was added PdCl₂dppf(100 mg, 0.12 mmol) and KOAc (808 mg, 8.2 mmol). The mixture was spargedwith nitrogen for 10 minutes, then the vessel was sealed and stirred at80° C. for 18 hours. The reaction mixture was partitioned between EtOAcand water, washed with brine, dried with magnesium sulfate, filtered,and concentrated via rotary evaporation. The crude material was purifiedvia flash chromatography on silica gel eluting with a gradient ofEtOAc/hexanes (5-20%) to obtain the target compound as a solid: MS(M+H)+ 388.3.

C.4-{4-[6-(6-Trifluoromethyl-pyridin-3-ylamino)-pyridin-3-yl]-phenyl}-piperidine-1-carboxylicacid tert-butyl ester

4-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl]-phenyl}-piperidine-1-carboxylicacid tert-butyl ester (1.56 g, 4.1 mmol) and(5-Bromo-pyridin-2-yl)-(6-trifluoromethyl-pyridin-3-yl)-amine (1.28 g,4.0 mmol) were dissolved in DME (8 mL) in a pressure vessel, and to thesolution was added PdCl₂dppf (100 mg, 0.12 mmol) and Na₂CO₃ (2.0M, 4.0mL, 8.1 mmol). The mixture was sparged with nitrogen for 10 minutes,then the vessel was sealed and stirred at 80° C. for 18 hours. Themixture was partitioned between EtOAc and saturated aqueous NH₄Cl,washed with brine, dried with magnesium sulfate, filtered, andconcentrated via rotary evaporation. The crude material was purified viacolumn chromatography on silica gel, eluting with a gradient ofEtOAc/hexanes (10-50%) to obtain the target compound as a solid: ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.25 (br. s., 2H) 1.42 (s, 9H) 1.52 (qd,J=12.63, 4.55 Hz, 2H) 1.77 (m, 2H) 2.66-2.76 (m, 1H) 4.09 (m, 2H) 7.03(d, J=8.59 Hz, 1H) 7.34 (d, J=8.34 Hz, 2H) 7.60 (d, J=8.08 Hz, 2H) 7.79(d, J=8.84 Hz, 1H) 7.99 (dd, J=8.72, 2.65 Hz, 1H) 8.56 (d, J=2.53 Hz,1H) 8.91 (d, J=2.53 Hz, 1H) 9.87 (s, 1H); MS (M+H)+ 499.3.

D.[5-(4-Piperidin-4-yl-phenyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine

4-{4-[6-(6-Trifluoromethyl-pyridin-3-ylamino)-pyridin-3-yl]-phenyl}-piperidine-1-carboxylicacid tert-butyl ester (1.02 g, 2.0 mmol) was slurried in1,4-dioxane/MeOH (5:1, 6 mL) and was treated with HCl (4M in1,4-dioxane, 2 mL). After 18 hours, added more HCl (4M, 1,4-dioxane, 3mL) and stirred 2 days. The solvents were removed via rotary evaporationand the crude was dried under vacuum to obtain the hydrochloride salt ofthe title compound as a sticky yellow solid which was used in the nextstep without further purification: MS (M+H)+ 399.4.

E.Oxo-(4-{4-[6-(6-trifluoromethyl-pyridin-3-ylamino)-pyridin-3-yl]-phenyl}-piperidin-1-yl)-aceticacid ethyl ester

[5-(4-Piperidin-4-yl-phenyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-yl)-aminehydrochloride (200 mg, 0.46 mmol) was slurried in DCM (2 mL) and to itwas added N,N-diisopropylethylamine (1.320 mL, 7.6 mmol).Chloro-oxo-acetic acid ethyl ester (0.076 mL, 0.69 mmol) was addeddropwise, and the reaction was stirred for 18 hours. The reactionmixture was partitioned between EtOAc and water, washed with brine,dried with magnesium sulfate, filtered, and concentrated via rotaryevaporation to obtain 229 mg of the title compound as a crude oil, whichwas taken to the next step without purification: MS (M+H)+ 499.2.

F.Oxo-(4-{4-[6-(6-trifluoromethyl-pyridin-3-ylamino)-pyridin-3-yl]-phenyl}-piperidin-1-yl)-aceticacid

Oxo-(4-{4-[6-(6-trifluoromethyl-pyridin-3-ylamino)-pyridin-3-yl]-phenyl}-piperidin-1-yl)-aceticacid ethyl ester (229 mg, 0.46 mmol) was dissolved in THF/MeOH/DMF(3:1:1, 5 mL) and to the solution was added aqueous LiOH (4M, 1 mL). Themixture was stirred at room temperature for 18 hours, then the reactionmixture was filtered and purified by reverse-phase preparative HPLC togive the title compound: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.41 (m, 1H)1.52 (m, 1H) 1.76 (td, J=13.89, 1.52 Hz, 2H) 2.72-2.81 (m, 1H) 2.96 (td,J=12.63, 2.27 Hz, 1H) 3.16 (d, J=5.31 Hz, 1H) 3.85 (dd, J=11.37, 2.27Hz, 1H) 4.37 (ddd, J=12.69, 1.83; 1.64 Hz, 1H) 7.03 (d, J=8.59 Hz, 1H)7.31 (d, J=8.34 Hz, 2H) 7.60 (d, J=8.34 Hz, 2H) 7.78 (d, J=8.84 Hz, 1H)7.98 (dd, J=8.72, 2.65 Hz, 1H) 8.55 (d, J=2.53 Hz, 1H) 8.58 (dd, J=8.59,2.02 Hz, 1H) 8.90 (d, J=2.27 Hz, 1H) 9.91 (s, 1H); MS (M+H)+ 471.2.

Example 4-14(4-Hydroxy-4-{4-[6-(6-trifluoromethyl-pyridin-3-ylamino)-pyridin-3-yl]-phenyl}-piperidin-1-yl)-aceticacid

A.(4-Hydroxy-4-{4-[6-(6-trifluoromethyl-pyridin-3-ylamino)-pyridin-3-yl]-phenyl}-piperidin-1-yl)-aceticacid ethyl ester

4-{4-[6-(6-Trifluoromethyl-pyridin-3-ylamino)-pyridin-3-yl]-phenyl}-piperidin-4-ol(153 mg, 0.37 mmol, prepared by analogous procedures described above)was dissolved in DMF (2 mL) and to it was added K₂CO₃ (128 mg, 0.93mmol) followed by bromo-acetic acid ethyl ester (0.050 mL, 0.44 mmol)added dropwise, and the reaction was stirred for 18 hours. The reactionmixture was partitioned between 40% EtOAc/hexanes and water, washed withbrine, dried with magnesium sulfate, filtered, and concentrated viarotary evaporation to obtain the title compound, as a crude oil, whichwas taken to the next step without purification: MS (M+H)+ 499.4.

B.(4-Hydroxy-4-{4-[6-(6-trifluoromethyl-pyridin-3-ylamino)-pyridin-3-yl]-phenyl}-piperidin-1-yl)-aceticacid

(4-Hydroxy-4-{4-[6-(6-trifluoromethyl-pyridin-3-ylamino)-pyridin-3-yl]phenyl}piperidin-1-yl)-aceticacid ethyl ester (137 mg, 0.27 mmol) was dissolved in THF/MeOH/DMF(3:1:1, 5 mL) and to the solution was added aqueous LiOH (4M, 1 mL). Themixture was stirred at room temperature for 18 hours, then the reactionmixture was filtered and purified by reverse-phase preparative HPLC togive the title compound: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.54 (qd,J=12.38, 4.29 Hz, 1H) 1.42 (qd, J=12.51, 4.42 Hz, 1H) 1.77 (td, J=14.08,1.14 Hz, 2H) 2.78 (m, 1H) 2.98 (td, J=12.63, 2.27 Hz, 1H) 3.29 (s, 2H)3.87 (dd, J=11.37, 2.27 Hz, 1H) 4.39 (ddd, J=12.69, 1.83, 1.64 Hz, 1H)7.04 (d, J=8.59 Hz, 1H) 7.32 (d, J=8.34 Hz, 2H) 7.61 (d, J=8.34 Hz, 2H)7.80 (d, J=8.84 Hz, 1H) 7.99 (dd, J=8.72, 2.65 Hz, 1H) 8.55-8.62 (m, 1H)8.57 (d, J=2.53 Hz, 1H) 8.92 (d, J=2.27 Hz, 1H) 9.93 (s, 1H); (M+H)+473.3.

Example 5-1(4-{4-[5-(6-Trifluoromethyl-pyridin-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid

A. {4-[4-(5-Bromo-pyridin-2-yl)-phenyl]-cyclohexyl}-acetic acid methylester

To a solution of{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclohexyl}-aceticacid methyl ester (4.0 g, 11.2 mmol, 1.0 equiv) and 2,5-dibromopyridine(3.2 g, 13.4 mmol, 1.2 equiv) in 50 Ml toluene/ethanol (1:1) was added 2M Na₂CO₃ (16.8 Ml, 3 equiv) followed by Pd(PPh₃)₄ (0.38 g, 0.34 mmol,0.03 equiv). The biphasic mixture was sparged with nitrogen for 10 min,then heated to 60° C. for 3 days. The reaction was cooled to roomtemperature and then partitioned between ethyl acetate and saturatedammonium chloride solution. The organic extracts were washed with brine,then dried over sodium sulphate and concentrated in vacuo. Purificationby silica gel chromatography (7-40% EtOAc in hexanes) afforded the titlecompound as a yellow solid: ¹H NMR (400 MHz, CDCl₃) δ 1.11 (dd, J=13.01,2.15 Hz, 2H) 1.41-1.54 (m, 2H) 1.76-1.90 (m, 5H) 2.20 (d, J=6.57 Hz, 2H)2.46 (tt, J=12.09, 3.19 Hz, 1H) 3.62 (s, 3H) 7.23 (d, J=8.08 Hz, 2H)7.53 (dd, J=8.59, 0.76 Hz, 1H) 7.77 (dd, J=8.46, 2.40 Hz, 1H) 7.81 (q,J=3.87 Hz, 1H) 7.81 (d, J=8.34 Hz, 1H) 8.64 (d, J=1.77 Hz, 1H); (M+H)+390.0.

B.(4-{4-[5-(6-Trifluoromethyl-pyridin-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid methyl ester

A microwave vial was charged with{4-[4-(5-bromo-pyridin-2-yl)-phenyl]-cyclohexyl}-acetic acid methylester (3.4 g, 8.8 mmol, 1.0 equiv), 3-amino-6-trifluoromethyl pyridine(2.1 g, 13.1 mmol, 1.2 equiv), cesium carbonate (7.1 g, 21.9 mmol, 2.5equiv), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-Phos,0.42 g, 0.88 mmol, 0.1 equiv) and palladium acetate (0.30 g, 0.44 mmol,0.05 equiv) in 20 Ml of toluene/t-butanol (9:1). The suspension wassparged with nitrogen for 10 min, then heated to 150° C. under microwaveheating for 45 min. The reaction was cooled to room temperature,partitioned between ethyl acetate and water. The organic extracts werewashed with brine, then dried over sodium sulphate and concentrated invacuo. Purification by silica gel chromatography afforded the titlecompound: ¹H NMR (400 MHz, DMSO-d6) δ 1.10-1.21 (m, 1H) 1.51 (qd,J=12.72, 2.78 Hz, 2H) 1.70-1.87 (m, 5H) 2.26 (d, J=6.57 Hz, 2H) 2.50 (m,1H) 3.61 (s, 3H) 7.33 (d, J=8.34 Hz, 2H) 7.65 (d, J=2.53 Hz, 1H)7.67-7.74 (m, 2H) 7.89 (d, J=8.59 Hz, 1H) 7.95 (d, J=8.34 Hz, 2H) 8.46(d, J=2.53 Hz, 1H) 8.54 (d, J=2.53 Hz, 1H) 9.18 (s, 1H); (M+H)+ 427.3.

C.(4-{4-[5-(6-Trifluoromethyl-pyridin-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid

A THF solution of(4-{4-[5-(6-trifluoromethyl-pyridin-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid methyl ester was treated with 10% aqueous LiOH and heated to 50° C.overnight. Upon reaction completion, the mixture was acidified withconcentrated HCl. The resulting precipitate was isolated by filtrationto afford the title compound: ¹H NMR (400 MHz, DMSO-d6) δ 1.08-1.19 (m,1H) 1.14 (dd, J=12.63, 2.27 Hz, 1H) 1.44-1.56 (m, 1H) 1.50 (dd, J=12.51,2.65 Hz, 1H) 1.75 (br. S., 1H) 1.84 (d, J=10.61 Hz, 4H) 2.14 (d, J=6.82Hz, 2H) 2.54 (m, 1H) 7.33 (d, J=8.34 Hz, 2H) 7.65 (d, J=2.53 Hz, 1H)7.68-7.74 (m, 1H) 7.70 (d, J=8.34 Hz, 1H) 7.89 (d, J=8.59 Hz, 1H) 7.95(d, J=8.59 Hz, 2H) 8.46 (d, J=2.78 Hz, 1H) 8.54 (d, J=2.53 Hz, 1H) 9.20(s, 1H); (M+H)+ 456.3. Alternatively, the methyl ester can be dissolvedin a mixture of THF and water, and treated with aqueous sodium hydroxide(4 equiv). The mixture can then be stirred at 50 degrees for 12 hours,at which point the THF is removed under reduced pressure to yield anopaque, white slurry, which affords the title compound as thecorresponding sodium salt upon filtration. ¹H NMR (DMSO-d6, 500 MHz) δ10.05 (s, 1H), 8.59 (d, 1H, J=2.8 Hz), 8.54 (s, 1H), 7.92 (d, 2H, J=8.2Hz), 7.86 (d, 1H, J=8.8 Hz), 7.75 (dd, 1H, J=8.7, 2.7 Hz), 7.69 (s, 2H),7.27 (d, 2 H, J=8.5 Hz), 2.45 (m, 1H), 1.84 (m, 4H), 1.67-1.80 (m, 3H),1.41 (m, 2H), 1.02 (m, 2H); MS m/z 456 (M−Na+2H)⁺.

Using the appropriate amino derivative, the following compounds may alsobe prepared:

MS Example Chemical Name LC rt Method (M + H)⁺ Ex. 5-2(4-{4-[5-(Pyridin-2-ylamino)-pyridin-2-yl]- 1.30 A 388.3phenyl}-cyclohexyl)-acetic acid Ex. 5-3{4-[4-(5-Phenylaminopyridin-2-yl)-phenyl]- 1.42 A 387.3cyclohexyl}-acetic acid Ex. 5-4(4-{4-[5-(5-Cyanopyridin-3-ylamino)-pyridin- 1.28 A 413.32-yl]-phenyl}-cyclohexyl)-acetic acid Ex. 5-5(4-{4-[5-{5-Trifluoromethylpyridin-2- 1.47 A 456.4ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)- acetic acid Ex. 5-6(4-{4-[5-(4-Trifluoromethylphenylamino)- 1.54 A 455.4pyridin-2-yl]-phenyl}-cyclohexyl)-acetic acid Ex. 5-7(4-{4-[5-(5-Methylpyridin-2-ylamino)-pyridin- 1.44 A 402.32-yl]-phenyl}-cyclohexyl)-acetic acid Ex. 5-8(4-{4-[5-(5-Trifluoromethylpyridin-2- 1.36 B 470.4ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)- acetic acid methyl ester Ex.5-9 (4-{4-[5-(5-Chloropyridin-2-ylamino)-pyridin- 1.48 A 422.32-yl]-phenyl}-cyclohexyl)-acetic acid Ex. 5-10(4-{4-[5-(6-Methoxypyridin-3-ylamino)- 1.35 A 418.4pyridin-2-yl]-phenyl}-cyclohexyl)-acetic acid Ex. 5-11(4-{4-[5-(5-Fluoropyridin-2-ylamino)-pyridin- 1.39 A 406.42-yl]-phenyl}-cyclohexyl)-acetic acid Ex. 5-12(4-{4-[5-(6-Acetylaminopyridin-3-ylamino)- 1.09 A 445.4pyridin-2-yl]-phenyl}-cyclohexyl)-acetic acid

Example 5-13{4-[4-(3-Methoxy-5-phenylamino-pyridin-2-yl)-phenyl]-cyclohexyl}-aceticacid

A. {4-[4-(3-Methoxy-5-nitro-pyridin-2-yl)-phenyl]-cyclohexyl}-aceticacid methyl ester

To a solution of 2-chloro-3-methoxy-5-nitro-pyridine (0.10 g, 0.53 mmol,1.0 equiv) and{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclohexyl}-aceticacid methyl ester (0.2 g, 0.56 mmol, 1.05 equiv) in 5 Ml DME was added0.5 Ml saturated potassium carbonate solution and 10 mg Pd(PPh₃)₄catalyst. The reaction was heated to 100° C. for 2 h. The crude reactionmixture was then concentrated in vacuo and then loaded directly onto asilica gel column. Elution with 30%

EtOAc/hexanes afforded the title compound: ¹H NMR (400 MHz, DMSO-d6) δppm 1.12-1.19 (m, 2H) 1.15 (d, J=13.14 Hz, 1H) 1.46-1.59 (m, 1H) 1.51(dd, J=12.38, 2.78 Hz, 2H) 1.81 (d, J=5.56 Hz, 4H) 2.26 (d, J=6.82 Hz,2H) 3.61 (s, 3H) 4.00 (s, 3H)

7.36 (d, J=8.34 Hz, 2H) 7.90 (d, J=8.34 Hz, 2H) 8.20 (d, J=2.02 Hz, 1H)9.05 (s, 1H); (M+H)+ 385.1.

B. {4-[4-(5-Amino-3-methoxy-pyridin-2-yl)-phenyl]-cyclohexyl}-aceticacid methyl ester

To a solution of{4-[4-(3-Methoxy-5-nitro-pyridin-2-yl)-phenyl]-cyclohexyl}-acetic acidmethyl ester (0.14 g) in 10 Ml EtOAc was added 30 mg Pd/C. The reactionvessel was purged with hydrogen, then stirred overnight under a balloonatmosphere of hydrogen. Filtration through Celite followed by removal ofsolvent in vacuo afforded the title compound: 1H NMR (400 MHz, DMSO-d6)δ ppm 0.94-1.02 (m, 1H) 1.01 (s, 3H) 1.31 (td, J=12.57, 9.98 Hz, 2H)1.64 (d, J=11.37 Hz, 4H) 2.09 (d, J=6.82 Hz, 2H) 3.44 (s, 3H) 3.59 (s,3H) 5.25 (s, 2H) 6.52 (d, J=2.02 Hz, 1H) 7.02 (d, J=8.34 Hz, 2H).7.47(d, J=2.02 Hz, 1H) 7.54 (d, J=8.34 Hz, 2H); (M+H)+ 355.1.

C.{4-[4-(3-Methoxy-5-phenylamino-pyridin-2-yl)-phenyl]-cyclohexyl}-aceticacid methyl ester

To a solution of{4-[4-(5-Amino-3-methoxy-pyridin-2-yl)-phenyl]-cyclohexyl}-acetic acidmethyl ester (0.12 g, 0.3 mmol, 1.0 equiv) and phenyl boronic acid(0.082 g, 0.67 mmol, 2.0 equiv) in 5 Ml dichloromethane was addedpyridine (0.054 Ml, 0.67 mmol, 2.0 equiv), copper (II) acetate (0.092 g,0.50 mmol, 1.5 equiv), and 4 Å molecular sieves. The heterogeneousreaction mixture was allowed to stir open to atmosphere for 18 h.Removal of solvent and purification by silica gel chromatography (40%EtOAc in hexanes) afforded the title compound: 1H NMR (400 MHz, DMSO-d6)δ ppm 1.14-1.31 (m, 2H) 1.50 (br. S., 1H) 1.55 (dd, J=12.51, 2.40 Hz,2H) 1.87 (d, J=12.38 Hz, 5H) 2.31 (d, J=6.57 Hz, 2H) 3.66 (s, 3H) 3.86(s, 3H) 6.96 (t, J=7.33 Hz, 1H) 7.20-7.38 (m, 7H) 7.82 (d, J=8.34 Hz,2H) 8.11 (d, J=2.02 Hz, 1H) 8.53 (s, 1H); (M+H)+ 431.2.

D.{4-[4-(3-Methoxy-5-phenylamino-pyridin-2-yl)-phenyl]-cyclohexyl}-aceticacid

To a solution of{4-[4-(3-Methoxy-5-phenylamino-pyridin-2-yl)-phenyl]-cyclohexyl}-aceticacid methyl ester (0.082 g) in 5 Ml THF was added 5 Ml of a 4 M LiOHsolution. The reaction was stirred overnight at room temperature, thenheated to 60° C. for 5 h. Acidification to Ph 1 using concentrated HClafforded a precipitate which was filtered to afford the title compound:1H NMR (400 MHz, DMSO-d6) δ ppm 1.02-1.13 (m, 1H) 1.07 (dd, J=12.38,2.27 Hz, 2H) 1.39-1.59 (m, J=12.88, 12.63, 12.63, 3.03 Hz, 3H) 1.77 (d,J=10.36 Hz, 4H) 2.09 (d, J=6.82 Hz, 2H) 3.84 (s, 3H) 7.00 (t, J=7.33 Hz,1H) 7.20-7.24 (m, 2H) 7.31 (dd, J=7.71, 1.89 Hz, 4H) 7.34 (s, 1H) 7.51(d, J=1.52 Hz, 1H) 7.61 (d, J=8.34 Hz, 2H) 7.91 (d, J=2.27 Hz, 1H) 9.27(br. S., 1H); (M+H)+ 417.1.

The following compounds may be prepared in analogous fashion:

MS Example Chemical Name LC rt Method (M + H)⁺ Ex. 5-14{4-[4-(3-Methoxy-5-(3- 1.4 A 435 fluorophenyl)amino-pyridin-2-yl)-phenyl]- cyclohexyl}-acetic acid Ex. 5-15{4-[4-(3-Methoxy- 1.5 A 485 5-(4-trifluoromethyl- phenyl)amino-pyridin-2-yl)-phenyl]-cyclo- hexyl}-acetic acid Ex. 5-16 {4-[4-(3-Methoxy-5-(3-1.5 A 451 chlorophenyl)amino-pyridin- 2-yl)-phenyl]-cyclo- hexyl}-aceticacid

Example 5-17(4-{4-[5-(3-Fluoro-phenylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid

A. {4-[4-(5-Nitro-pyridin-2-yl)-phenyl]-cyclohexyl}-acetic acid methylester

To a solution of 2-bromo-5-nitropyridine (0.81 g, 4.0 mmol, 1.0 equiv)and{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclohexyl}-aceticacid methyl ester (1.5 g, 4.0 mmol, 1.05 equiv) in 20 Ml DME was added 2Ml saturated potassium carbonate solution followed by 50 mg Pd(PPh₃)₄catalyst. The reaction was then heated to 80° C. over the weekend.Removal of volatiles in vacuo followed by silica gel chromatography (20%EtOAc in hexanes) afforded the title compound: 1H NMR (400 MHz, DMSO-d6)δ ppm 0.94-1.06 (m, 1H) 1.00 (dd, J=12.76, 2.15 Hz, 2H) 1.30-1.42(m,J=12.82, 12.60, 12.60, 2.91 Hz, 2H) 1.65 (br. S., 2H) 1.68 (d, J=3:54Hz, 3H) 2.11 (d, J=6.82 Hz, 2H) 3.46 (s, 3H) 7.27 (d, J=8.34 Hz, 2H)7.98 (d, J=8.34 Hz, 2H) 8.08 (dd, J=8.84, 0.51 Hz, 1H) 8.47 (dd,J=8.84,2.78 Hz, 1H) 9.27 (d, J=2.27 Hz, 1H) (M+H)+ 355.1.

B. {4-[4-(5-Amino-pyridin-2-yl)phenyl]-cyclohexyl}-acetic acid methylester

To a solution of {4-[4-(5-Nitro-pyridin-2-yl)-phenyl]-cyclohexyl}-aceticacid methyl ester (1.4 g, 4.0 mmol) in 20 Ml EtOH was added Pd/C (0.4 g)followed by ammonium formate (2 g). The reaction mixture was heated toreflux for 4 h, then cooled to room temperature and filtered throughCelite. Removal of solvent in vacuo afforded the title compound: 1H NMR(400 MHz, DMSO-d6) δ ppm 1.08-1.20 (m, 2H) 1.43-1.54 (m, 1H) 1.48 (dd,J=12.57, 2.46 Hz, 2H) 1.81 (d, J=11.75 Hz, 6H) 2.26 (d, J=6.69 Hz, 2H)3.61 (s, 3H) 6.98 (dd, J=8.59, 2.78 Hz, 1H) 7.24 (d, J=8.34 Hz, 2H) 7.57(d, J=8.59 Hz, 1H) 7.81 (d, J=8.34 Hz, 2H) 8.00 (d, J=2.65 Hz, 1H);(M+H)+ 325.2.

C.(4-{4-[5-(3-Fluoro-phenylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid methyl ester

To a solution of {4-[4-(5-amino-pyridin-2-yl)-phenyl]-cyclohexyl}-aceticacid methyl ester (0.10 g, 0.3 mmol, 1.0 equiv) and 3-fluorophenylboronic acid (0.086 g, 0.61 mmol, 2.0 equiv) in 5 Ml dichloromethane wasadded pyridine (0.05 Ml, 0.61 mmol, 2.0 equiv), copper (II) acetate(0.084 g, 0.46 mmol, 1.5 equiv) and 4 Å molecular sieves. Theheterogeneous mixture was allowed to stir open to atmosphere for 18 h.Purification by silica gel chromatography (20-45% EtOAc in hexanes)afforded the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12-1.27(m, 2H) 1.47 (br. S., 1H) 1.53 (dd, J=12.51, 2.65 Hz, 1H) 1.67 (br. S.,1H) 1.85 (d, J=12.38 Hz, 4H) 2.29 (d, J=6.57 Hz, 2H) 3.34 (s, 2H) 3.64(s, 3H) 6.69 (td, J=8.46, 2.53 Hz, 1H) 6.89 (dt, J=11.62, 2.15 Hz, 1H)6.96 (dd, J=7.83, 1.77 Hz, 1H) 7.33 (d, J=8.34 Hz, 2H) 7.63 (dd, J=8.59,2.78 Hz, 1H) 7.84 (d, J=8.59 Hz, 1H) 7.95 (d, J=8.34 Hz, 2H) 8.47 (s,1H) 8.71 (s, 1H); (M+H)+ 419.3.

D.(4-{4-[5-(3-Fluoro-phenylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid

To a solution of(4-{4-[5-(3-Fluoro-phenylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid methyl ester (0.10 g) in 5 Ml THF was added 5 Ml of a 4 M LiOHsolution. The reaction was stirred overnight at room temperature, thenheated to 60° C. overnight. Acidification to Ph 1 using concentrated HClafforded a precipitate which was filtered to afford the title compound:1H NMR (400 MHz, DMSO-d6) δ ppm 0.95-1.12 (m, 1H) 1.02 (dd, J=11.62,9.35 Hz, 2H) 1.33 (br. S., 1H) 1.38 (dd, J=12.51, 2.65 Hz, 2H) 1.62 (d,J=9.35 Hz, 2H) 1.71 (d, J=10.11 Hz, 4H) 2.03 (d, J=6.82 Hz, 2H)6.64-6.73 (m, 1H) 6.86-6.93 (m, 2H) 7.29 (d, J=8.34 Hz, 2H) 7.21-7.35(m, 1H) 7.78 (d, J=8.34 Hz, 2H) 7.83-7.89 (m, 1H) 7.89-7.97 (m, 1H) 8.30(s, 1H) 9.26 (br. S., 1H); (M+H)+ 405.1.

The following compounds may be prepared in analogous fashion:

MS Example Chemical Name LC rt Method (M + H)⁺ Ex. 5-18(4-{4-[5-(3-Chloro-phenyl- 1.5 10 421.1 amino)-pyridin-2-yl]-phenyl}-cyclohexyl)-acetic acid

Example 5-19 (4-{4-[5-(1-Methyl-1H-pyrazol-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-acetic acid

A. (6-Bromo-pyridin-3-yl)-(1-methyl-1H-pyrazol-3-yl)-amine

To a solution of 1-methyl-1H-pyrazol-3-ylamine (0.23 g, 2.3 mmol, 1.0equiv) and 2-bromopyridyl-5-boronic acid (0.70 g, 3.5 mmol, 1.5 equiv)in 10 Ml dichloromethane was added pyridine (0.43 Ml, 5.4 mmol, 2.4equiv), copper (II) acetate (0.63 g, 3.5 mmol, 1.5 equiv) and 4 Åmolecular sieves. The heterogeneous reaction mixture was allowed to stirvigorously open to air overnight. The reaction was then filtered throughCelite, concentrated in vacuo, and purified by silica gel chromatographyto afford the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 3.80 (s,3H) 5.84 (s, 1H) 7.45 (d, J=8.59 Hz, 1H) 7.60 (d, J=2.02 Hz,1H) 7.86(dd, J=8.59, 3.03 Hz, 1H) 8.41 (d, J=2.78 Hz, 1H) 8.92 (s, 1.H); (M+H)+255.1.

B.(4-{4-[5-(1-Methyl-1H-pyrazol-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid methyl ester

To a solution of (6-bromo-pyridin-3-yl)-(1-methyl-1H-pyrazol-3-yl)-amine(0.15 g, 0.6 mmol, 1.0 equiv) and{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclohexyl}-aceticacid methyl ester (0.23 g, 0.7 mmol, 1.1 equiv) in 5 Ml DME was added0.5 Ml saturated potassium carbonate solution followed by 5 mg Pd(PPh₃)₄catalyst. The reaction was then heated to 80° C. for 2 h. Removal ofvolatiles in vacuo followed by silica gel chromatography (20% EtOAc inhexanes) afforded the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm1.14-1.26 (m, 2H) 1.54 (qd, J=12.59, 2.40 Hz, 2H) 1.68 (br. S., 1H) 1.87(d, J=11.12 Hz, 5H) 2.31 (d, J=6.57 Hz, 2H) 3.66 (s, 3H) 3.82 (s, 3H)5.86 (s, 1H) 7.33 (d, J=8.34 Hz, 2H) 7.59 (d, J=2.02 Hz, 1H) 7.80 (d,J=8.84 Hz, 1H) 7.93 (d, J=8.34 Hz, 2H) 7.97 (dd, J=8.84, 2.78 Hz, 1H)8.65 (d, J=2.27 Hz, 1H) 8.83 (s, 1H); (M+H)+ 405.2.

C. (4-{4-[5-(1-Methyl-1H-pyrazol-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-acetic acid

To a solution of(4-{4-[5-(1-Methyl-1H-pyrazol-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid methyl ester (0.12 g) in 5 Ml THF was added 5 Ml of a 4 M LiOHsolution. The reaction was stirred overnight at room temperature, thenheated to 60° C. overnight. Acidification to Ph 1 using concentrated HClafforded a precipitate which was filtered to afford the title compound:1H NMR (400 MHz, DMSO-d6) δ ppm 1.02-1.13 (m, 2H) 1.40-1.59 (m, J=12.82,12.66, 12.66, 3.03 Hz, 3H) 1.77 (d, J=9.60 Hz, 5H) 2.09 (d, J=6.82 Hz,2H) 2.48-2.54 (m, 1H) 3.74 (s, 3H) 5.84 (s, 1H) 7.38 (d, J=8.34 Hz, 2H)7.58 (s, 1H) 7.83 (d, J=8.34 Hz, 2H) 8.09 (d, J=9.09 Hz, 1H) 8.23 (d,J=11.62 Hz, 1H) 8.88(s, 1H) 9.79 (br. S., 1H); (M+H)+ 391.1.

The following compounds may be prepared in analogous fashion:

MS Example Chemical Name LC rt Method (M + H)⁺ Ex. 5-20(4-{4-[5-(Isoxazol-3- 1.2 A 378.1 ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-acetic acid

Example 5-21(4-{4-[5-(5-Fluoro-6-methoxy-pyridin-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid

A. (6-Bromo-pyridin-3-yl)-(5-fluoro-6-methoxy-pyridin-3-yl)-amine

To a solution of 6-bromo-pyridin-3-ylamine (0.20 g, 1.2 mmol, 1.0 equiv)and 2-methoxy-3-fluoropyridyl-5-boronic acid (0.39 g, 2.3 mmol, 2.0equiv) in 10 Ml dichloromethane was added pyridine (0.24 Ml, 3.0 mmol,2.5 equiv), copper (II) acetate (0.32 g, 1.7 mmol, 1.5 equiv) and 4 Åmolecular sieves. The heterogeneous reaction mixture was allowed to stirvigorously open to air overnight. The reaction was then filtered throughCelite, concentrated in vacuo, and purified by silica gel chromatographyto afford the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 3.96 (s,3H) 7.35 (d, J=3.03 Hz, 1H) 7.37 (d, J=3.03 Hz, 1H) 7.42-7.46 (m, 1H)7.62 (dd, J=11.87, 2.27 Hz, 1H) 7.88 (d, J=2.53 Hz, 1H) 8.09 (s, 1H)8.52 (s, 1H); (M+H)+ 300.0.

B.(4-{4-[5-(5-Fluoro-6-methoxy-pyridin-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid methyl ester

To a solution of(6-bromo-pyridin-3-yl)-(5-fluoro-6-methoxy-pyridin-3-yl)-amine (0.17 g,0.6 mmol, 1.0 equiv) and{4-[4-(4,4,5,5-tetramethyl-(1,3,2]dioxaborolan-2-yl)-phenyl]-cyclohexyl}-aceticacid methyl ester (0.22 g, 0.6 mmol, 1.0 equiv) in 15 Ml DME was added 1Ml saturated sodium carbonate solution followed by 10 mg Pd(PPh₃)₄catalyst. The reaction was then heated to 80° C. overnight. Removal ofvolatiles in vacuo followed by silica gel chromatography (20% EtOAc inhexanes) afforded the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm0.93-1.08 (m, 1H) 1.01 (d, J=2.78 Hz, 1H) 1.31-1.52 (m, 3.H) 1.62 (s,2H) 1.69 (d, J=9.85 Hz, 4H) 2.02 (d, J=7.07 Hz, 2H) 3.81 (s, 3H) 7.28(d, J=8.34 Hz, 2H) 7.58 (d, J=13.89 Hz, 1H) 7.75 (d, J=8.34 Hz, 3H) 7.70(d, J=8.59 Hz, 1H) 7.81 (d, J=2.27 Hz, 1H) 7.89 (d, J=8.84 Hz, 1H) 8.15(s, 1H) 9.04 (br. S., 1H); (M+H)+ 450.3.

C.(4-{4-[5-(5-Fluoro-6-methoxy-pyridin-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid

Using the saponification procedures outlined above, the title compoundwas produced: 1H NMR (400 MHz, DMSO-d6) δ ppm 0.93-1.08 (m, 1H) 1.01 (d,J=2.78 Hz, 1H) 1.31-1.52 (m, J=12.95, 12.66, 12.66, 3.16 Hz, 3H) 1.62(s, 2H) 1.69 (d, J=9.85 Hz, 4H) 2.02 (d, J=7.07 Hz, 2H) 3.81 (s, 3H)7.28 (d, J=8.34 Hz, 2H) 7.58. (d, J=13.89 Hz, 1H) 7.75 (d, J=8.34 Hz,3H) 7.70 (d, J=8.59 Hz, 1H) 7.81 (d, J=2.27 Hz, 1H) 7.89 (d, J=8.84 Hz,1H) 8.15 (s, 1H) 9.04 (br. S., 1H); (M+H)+ 436.1.

Example 5-22(4-{5-[5-(6-Trifluoromethyl-pyridin-3-ylamino)-pyridin-2-yl]-spirocyclohexylidenyl-1,1′-indanyl}-aceticacid

A. (6-Bromo-pyridin-3-yl)-(6-trifluoromethyl-pyridin-3-yl)-amine

To a solution of 3-amino-6-trifluoromethyl pyridine (0.25 g, 1.2 mmol,2.0 equiv) and 2-bromopyridyl-5-boronic acid (0.10 g, 0.62 mmol, 1.0equiv) in 5 Ml dichloromethane was added pyridine (0.10 Ml, 1.2 mmol,2.0 equiv), copper (II) acetate (0.17 g, 0.93 mmol, 1.5 equiv) and 4 Åmolecular sieves. The heterogeneous reaction mixture was allowed to stirvigorously open to air overnight. The reaction was then filtered throughCelite, concentrated in vacuo, and purified by silica gel chromatographyto afford the title compound: (M+H)+ 319.9.

B.(4-{5-[5-(6-Trifluoromethyl-pyridin-3-ylamino)-pyridin-2-yl]spirocyclohexylidenyl-1,1′-indanyl}-aceticacid methyl ester

A microwave vial was charged with(6-Bromo-pyridin-3-yl)-(6-trifluoromethyl-pyridin-3-yl)-amine (0.087 g,0.28 mmol, 1.0 equiv) and{4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)]-spirocyclohexylidenyl-1,1′-indanyl}-aceticacid methyl ester (0.10 g, 0.28 mmol, 1.0 equiv) in 3 Mldimethoxyethane. To this solution was added 2M Na2CO3 (0.35 Ml, 2.5equiv) followed by PdCl₂dppf(dichloromethane) complex (0.011 g, 0.014mmol, 0.05 equiv). The mixture was sparged with nitrogen for 5 minutesand then heated to 150° C. for 30 min. The reaction was partitionedbetween EtOAc and water, and the organic extracts were washed with brineand dried over magnesium sulphate. Purification of the crude product byflash chromatography afforded the title compound: (M+H)+ 494.2.

C.(4-{5-[5-(6-Trifluoromethyl-pyridin-3-ylamino)-pyridin-2-yl]-spirocyclohexylidenyl-1,1′-indanyl}-aceticacid

A solution of(4-{5-[5-(6-Trifluoromethyl-pyridin-3-ylamino)-pyridin-2-yl]-spirocyclohexylidenyl-1,1′-indanyl}-aceticacid methyl ester (0.020 g, 0.041 mmol, 1.0 equiv) in 1.5 Ml DMF wascharged with 0.5 Ml of a 10% LiOH solution. The homogeneous solution washeated to 60° C. for 3 h. Purification by reverse-phase HPLC affordedthe title compound: ¹H NMR (400 MHz, DMSO-d6) δ 1.62-1.79 (m, 4H)2.01-2.10 (m, 1H) 2.14 (td, J=7.58, 1.01 Hz, 2H) 2.31-2.44 (m, 2H) 2.95(t, J=7.33 Hz, 2H) 3.79 (d, J=14.15 Hz, 1H) 5.63 (s, 1H) 7.25 (d, J=7.83Hz, 1H) 7.65 (d, J=2.53 Hz, 1H) 7.68-7.74 (m, 2H) 7.82 (d, J=8.08 Hz,1H) 7.88 (br. S., 1H) 7.86 (d, J=4.04 Hz, 1H) 8.46 (d, J=2.53 Hz, 1H)8.53 (d, J=3.03 Hz, 1H) 9.20 (s, 1H); (M+H)+ 480.2.

Example 5-23(4-{4-[5-(Benzooxazol-2-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid

A.(4-{4-[5-(Benzooxazol-2-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid methyl ester

65 mg of {4-[4-(5-Amino-pyridin-2-yl)-phenyl]-cyclohexyl)-acetic acidmethyl ester and 0.3 Ml of 2-chlorobenzoxazole were dissolved in 1.5 Mlof t-BuOH/DME (1:1) in a 5 Ml microwave tube with a stirring bar. 0.1 Mlof 4N-HCl in dioxane was added and the reaction vessel was sealed andheated at 120° C. for 2 hours by microwave. The reaction was dilutedwith ethyl acetate and the resulting precipitates were filtered andwashed with ethyl acetate. The filter cake was dried by air in thesuction funnel and analyzed by ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.2 (s,3H) 1.5 (s, 2H) 1.8 (s, 6H) 2.3 (d, J=6.8 Hz, 2H) 3.6 (s, 4H) 7.2 (m,1H) 7.3 (m, 1H) 7.3 (d, J=8.3 Hz, 2H) 7.5 (d, J=13.9 Hz, 2H) 8.0 (m, 3H)8.4 (m, 1H) 8.9 (d, J=2.3 Hz, 1H) 11.0 (s, 1H); (M+H)+ 442.2.

B.(4-{4-[5-(Benzooxazol-2-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid(4-{4-[5-(Benzooxazol-2-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid methyl ester was stirred in 4 Ml of THF/water (1:1) and treatedwith 30 mg of LiOH at ambient temperature. The reaction was then heatedat 50° C. and stirred overnight. LC-MS analysis indicated the reactionwas complete. The reaction was diluted with water (2 Ml) and neutralizedwith 6N HCl. The resulting precipitate was filtered and washed withwater and ethyl acetate. The precipitate was dried and analyzed by 1HNMR (400 MHz, DMSO-D6) δ ppm 1.1 (m, 2H) 1.5 (s, 2H) 1.8 (t, J=6.7 Hz,1H) 1.8 (s, 4H) 2.2 (d, J=6.8 Hz, 2H) 7.2 (td, J=7.8, 1.3 Hz, 1H) 7.3(td, J=7.6, 1.1 Hz, 1H) 7.3 (d, J=8.3 Hz, 2 H) 7.5 (dd, J=13.9, 7.3 Hz,2H) 8.0 (d, J=8.1 Hz, 3H) 8.3 (dd, J=8.7, 2.7 Hz, 1H) 8.9 (d, J=3.0 Hz,1H); (M+H)+ 428.1.

Alternatively, the methyl ester can be dissolved in THF and treated withaqueous sodium hydroxide (4 equiv). The mixture can then be stirred at50 degrees for 12 hours, at which point water may be added and most ofthe organic solvent may be removed under reduced pressure. Addition ofacetonitrile followed by cooling may yield a precipitate which can beisolated by filtration to afford the title compound as the correspondingsodium salt: ¹H NMR (DMSO-d6, 500 MHz) δ 8.73 (s, 1H), 8.29 (dd, 1H,J=8.7, 2.7 Hz), 7.86 (d, 2H, J=8.2 Hz), 7.81 (d, 1H, J=8.8 Hz), 7.31 (m,2H), 7.21 (d, 2H, J=8.2 Hz), 7.09 (t, 1H, J=7.6 Hz), 6.97 (t, 1H, J=7.7Hz), 2.40 (m, 1H), 1.83 (d, 2H, J=6.9 Hz), 1.75 (m, 4H), 1.65 (m, 1H),1.40 (m, 2H), 1.02 (m, 2H); MS ink 428 (M−Na+2H)⁺.

Example 5-24(4-{4-[5-(2,2-Dimethyl-propionylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid

A. (4-{4-85-(2,2-Dimethyl-propionylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid methyl ester

To a mixture of {4-[4-(5-amino-pyridin-2-yl)-phenyl]-cyclohexylyaceticacid methyl ester (100 mg, 0.3 mmol) in methylene chloride (10 ml) wasadded triethylamine (43 ul, 0.3 mmol) and trimethylacetyl chloride (40ul, 0.3 mmol). After 15 hours at room temperature, the reaction wasdiluted with hexanes to afford a precipitate which was collected byfiltration: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15 (dd, J=12.69, 1.71 Hz,2H) 1.26 (s, 10H) 1.42-1.56 (m, 1H)1.50 (d, J=9.85 Hz, 1H) 1.82 (d,J=11.37 Hz, 5H) 2.26 (d, J=6.69 Hz, 2H) 3.61 (s, 3H) 7.32 (d, J=8.34 Hz,2H) 7.87 (d, J=8.72 Hz, 1H) 7.95 (d, J=8.34 Hz, 2H) 8.15 (dd, J=8.72,2.53 Hz, 1H) 8.88 (d, J=2.53 Hz, 1H)9.53 (s, 1H); (M+H)+ 409.2.

B.(4-{4-[5-(2,2-Dimethyl-propionylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid

A mixture of(4-{4-[5-(2,2-dimethyl-propionylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid methyl ester (90 mg, 0.2 mmol) was stirred for 15 hours in a 1:1mixture of THF/4M LiOH (10 ml). Neutralization with concentrated. HClafforded a precipitate which was isolated by filtration:. 1H NMR (400MHz, DMSO-d6) δ ppm 1.02 (dd, J=12.25, 1.89 Hz, 2H) 1.19 (s, 10H) 1.41(dd, J=12.44, 2.59 Hz, 2H) 1.77 (t, J=13.14 Hz, 6H) 1.95 (d, J=6.95 Hz,2H) 7.24 (d, J=8.34 Hz, 2H) 7.78 (d, J=8.72 Hz, 1H) 7.87 (d, J=8.34 Hz,2H) 8.09 (dd, J=8.72, 2.53 Hz, 1H) 8.83 (d, J=2.40 Hz,1H) 9.52 (s, 1H);(M+H)+ 395.1.

Example 5-25[4-(4-{5-[3-(4-Trifluoromethoxy-phenyl)-ureido]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid

To 150 mg (0.5 mmol){4-[4-(5-Amino-pyridin-2-yl)-phenyl]-cyclohexyl}-acetic acid methylester in 5 mL DCM, 102 mg (0.5 mmol)1-Isocyanato-4-trifluoromethoxy-benzene was added and the resultingmixture was stirred at room temperature over night. Dilution of reactionmixture with hexanes caused desired product to precipitate which wascollected by filtration to afford[4-(4-{5-[3-(4-Trifluoromethoxy-phenyl)-ureido]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid methyl ester: M+1=528.2. ¹H NMR (400 MHz, DMSO-D6) δ ppm 1.09-1.20(m, 2H) 1.50 (td, J=12.63, 10.11 Hz, 2H) 1.80 (s, 3H)1.83 (d, J=3.28 Hz,2H) 2.25 (d, J=6.82 Hz, 2H) 2.51-2.54 (m, 1H) 3.61 (s, 3H) 7.31 (dd,J=8.72, 3.16 Hz, 4H) 7.55-7.61 (m, 2H) 7.86 (d, J=8.59 Hz, 1H) 7.94 (d,J=8.34 Hz, 2H) 8.02 (dd, J=8.72, 2.65 Hz, 1H) 8.66 (d, J=2.78 Hz, 1H)8.99 (s, 1H) 9.05 (s, 1H).

To 210 mg (0.4 mmol)[4-(4-{5-[3-(4-Trifluoromethoxy-phenyl)ureido]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid methyl ester in THF/H₂O (10 mL; 4:1), 5 mL (4M) aqueous LithiumHydroxide solution was added and the mixture stirred at 60° C. for 5hours. Acidified with concentrated hydrochloric acid which precipitatedthe desired compound. Filtered and dried under vacuum to afford[4-(4-{5-[3-(4-Trifluoromethoxy-phenyl)-ureido]-pyridin-2-yl)-phenyl)-cyclohexyl]-aceticacid, which was subsequently dissolved in methanol (5 mL) one equivalentof potassium hydroxide and 2 mL of H₂O were added and the resultingmixture was stirred at 40° C. for 2 hours. Evaporated to dryness toafford[4-(4-{5-[3-(4-Trifluoromethoxy-phenyl)-ureido]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid as the potassium salt: ¹H NMR (400 MHz, MeOD) δ ppm 1.03-1.14 (m,2H) 1.45 (td, J=12.57, 9.98 Hz, 2H) 1.75-1.87 (m, 5H) 2.03 (d, J=7.07Hz, 2 H) 2.37-2.47 (m, 1H) 7.12 (d, J=8.34 Hz, 2H) 7.21 (d, J=8.34 Hz,2H) 7.43-7.51 (m, 2H) 7.64-7.73 (m, 3H) 7.96 (dd, J=8.72, 2.65 Hz, 1H)8.58 (d, J=2.27 Hz, 1H); (M+H)+ 514.2.

Using analogous procedures to those described above, the followingcompounds may also be prepared:

Example # Name LC rt Method (M + H)+ Ex. 5-26{4-[4-{5-Acetylamino-pyridin-2-yl)-phenyl]- 1.11 A 353.2cyclohexyl}-acetic acid Ex. 5-27(4-{4-[5-(3-Trifluoromethyl-benzoylamino)- 1.53 A 483.2pyridin-2-yl]-phenyl}-cyclohexyl)-acetic acid Ex. 5-28[4-(4-{5-[(Pyridine-2-carbonyl)-amino]-pyridin- 1.4 A 416.22-yl}-phenyl)-cyclohexyl]-acetic acid Ex. 5-29[4-(4-{5-{3-(2-Trifluoromethyl-phenyl)-ureido]- 12.9 D 498.2pyridin-2-yl}-phenyl)-cyclohexyl]-acetic acid Ex. 5-30(4-{4-[5-(3-o-Tolyl-ureido)-pyridin-2-yl]- 12 D 444.2phenyl}-cyclohexyl)-acetic acid Ex. 5-31[4-(4-{5-[(1-Methyl-1H-indole-3-carbonyl)- 12.5 D 468.2amino]-pyridin-2-yl}-phenyl)-cyclohexyl]- acetic acid Ex. 5-32[4-(4-{5-[(1H-Indole-3-carbonyl)-amino]- 11.9 D 454.2pyridin-2-yl}-phenyl)-cyclohexyl]-acetic Ex. 5-33[4-(4-{5-[(Pyridine-3-carbonyl)-amino]-pyridin- 9.8 D 416.12-yl}-phenyl)-cyclohexyl]-acetic acid Ex. 5-34[4-(4-{5-[(6-Methyl-pyridine-3-carbonyl)- 9.6 D 430.1amino]-pyridin-2-yl}-phenyl)-cyclohexyl]- acetic acid Ex. 5-35[4-(4-{5-{(5-Bromo-pyridine-3-carbonyl)- 12 D 495.8amino]-pyridin-2-yl}-phenyl)-cyclohexyl]- acetic acid Ex. 5-36[4-(4-{5-{(5-Chloro-6-methoxy-pyridine-3- 1.42 A 480carbonyl)-amino]-pyridin-2-yl}-phenyl)- cyclohexyl]-acetic acid Ex. 5-37[4-(4-{5-[(5-Isobutyl-isoxazole-3-carbonyl)- 13.9 D 462.1amino]-pyridin-2-yl}-phenyl)-cyclohexyl]- acetic acid Ex. 5-38[4-(4-{5-[(3-tert-Butyl-1-methyl-1H-pyrazole- 13.2 D 475.24-carbonyl)-amino]-pyridin-2-yl}-phenyl)- cyclohexyl]-acetic acid Ex.5-39 [4-(4-{5-{(5-tert-Butyl-1H-pyrazole-3- 12.3 D 461.2carbonyl)-amino]-pyridin-2-yl}-phenyl)- cyclohexyl]-acetic acid Ex. 5-40[4-(4-{5-[(5-Isopropyl-isoxazole-3-carbonyl)- 13.2 D 448.2amino]-pyridin-2-yl}-phenyl)-cyclohexyl]- acetic acid Ex. 5-41{4-{4-(5-Isobutoxycarbonylamino-pyridin-2- 12.4 D 411.1yl)-phenyl]-cyclohexyl}-acetic acid Ex. 5-42[4-(4-{5-{((S)-5-Oxo-pyrrolidine-2-carbonyl)- 9.4 D 422.1amino]-pyridin-2-yl}-phenyl)-cyclohexyl]- acetic acid Ex. 5-43(4-{4-[5-{4-Fluoro-3-trifluoromethyl- 1.51 A 501.2benzoylamino)-pyridin-2-yl]-phenyl}- cyclohexyl)-acetic acid Ex. 5-44(4-{4-[5-(4-Trifluoromethyl-benzoylamino)- 1.49 A 482.9pyridin-2-yl]-phenyl}-cyclohexyl)-acetic acid Ex. 5-45[4-(4-{5-[(6-Trifluoromethyl-pyridine-3- 1.39 A 483.9carbonyl)-amino]-pyridin-2-yl}-phenyl)- cyclohexyl]-acetic acid Ex. 5-46(4-{4-[5-(3-Fluoro-5-trifluoromethyl- 1.56 A 501benzoylamino)-pyridin-2-yl]-phenyl}- cyclohexyl)-acetic acid Ex. 5-47[4-(4-{5-[(Tetrahydro-pyran-4-carbonyl)- 1.12 A 422.9amino]-pyridin-2-yl}-phenyl)-cyclohexyl]- acetic acid Ex. 5-48[4-(4-{5-[(5-Bromo-2-methoxy-pyridine-3- 1.55 A 523.9carbonyl)-amino]-pyridin-2-yl}-phenyl)- cyclohexyl]-acetic acid Ex. 5-49[4-(4-{5-[(1,5-Dimethyl-1H-pyrazole-3- 1.24 A 432.9carbonyl)-amino]-pyridin-2-yl}-phenyl)- cyclohexyl]-acetic acid Ex. 5-50[4-(4-{5-[(5-Methoxy-1H-indole-3-carbonyl)- 11.9 D 484.1amino]-pyridin-2-yl}-phenyl)-cyclohexyl]- acetic acid Ex. 5-51[4-(4-{5-[(2,5-Dimethyl-1H-pyrrole-3- 11.3 D 432.1carbonyl)-amino]-pyridin-2-yl}-phenyl)- cyclohexyl]-acetic acid Ex. 5-52[4-(4-{5-[(1-Methyl-5-trifluoromethyl-1H- 11.8 D 487pyrazole-4-carbonyl)-amino]-pyridin-2-yl}- phenyl)-cyclohexyl]-aceticacid Ex. 5-53 {4-[4-(5-{[4-(Morpholine-4-sulfonyl)-1H- 11.1 D 553.1pyrrole-2-carbonyl]-amino}-pyridin-2-yl)- phenyl]-cyclohexyl}-aceticacid Ex. 5-54 (4-{4-{5-(2-Fluoro-2-methyl-propionylamino)- 1.15 A 398.9pyridin-2-yl]-phenyl}-cyclohexyl)-acetic acid Ex. 5-55[4-(4-{5-[(1-Methyl-3-trifluoromethyl-1H- 13.5 D 501.2pyrazole-4-carbonyl)-amino]-pyridin-2-yl}- phenyl)-cyclohexyl]-aceticacid methyl ester Ex. 5-56 (4-{4-[5-(2-Methyl-2-pyrazol-1-yl- 1.18 A447.3 propionylamino)-pyridin-2-yl]-phenyl}- cyclohexyl)-acetic acid Ex.5-57 [4-(4-{5-[(5-Isopropyl-isoxazole-4-carbonyl)- 12 D 448.3amino]-pyridin-2-yl}-phenyl)-cyclohexyl]- acetic acid Ex. 5-58[4-(4-{5-[(1-Methyl-3-trifluoromethyl-1H- 11.8 D 487.3pyrazole-4-carbonyl)-amino]-pyridin-2-yl}- phenyl)-cyclohexyl]-aceticacid Ex. 5-59 [4-(4-{5-[(5-Cyclopropyl-isoxazole-4- 3.2 E 446carbonyl)-amino]-pyridin-2-yl}-phenyl)- cyclohexyl]-acetic acid Ex. 5-60[4-(4-{5-[(5-Cyclopropyl-isoxazole-4- 13.7 D 460.2carbonyl)-amino]-pyridin-2-yl}-phenyl)- cyclohexyl]-acetic acid methylester Ex. 5-61 [4-(4-{5-[(5-Cyclopropyl-isoxazole-3- 4.01 E 446carbonyl)-amino]-pyridin-2-yl}-phenyl)- cyclohexyl]-acetic acid Ex. 5-62[4-(4-{5-[(6-Methoxy-pyridine-3-carbonyl)- 1.26 A 446amino]-pyridin-2-yl}-phenyl)-cyclohexyl]- acetic acid Ex. 5-63(4-{4-{5-(2,2-Dimethyl-butyrylamino)-pyridin- 1.4 A 4092-yl]-phenyl}-cyclohexyl)-acetic acid Ex. 5-64(4-{4-[5-(2-Methoxy-2-methyl- 1.17 A 411propionylamino)-pyridin-2-yl]-phenyl}- cyclohexyl)-acetic acid Ex. 5-65[4-(4-{5-[(1,5-Dimethyl-1H-pyrazole-4- 3.58 E 433carbonyl)-amino]-pyridin-2-yl}-phenyl)- cyclohexyl]-acetic acid Ex. 5-66(4-{4-{5-(Tetrahydro-pyran-4- 3.35 E 439yloxycarbonylamino)-pyridin-2-yl]-phenyl}- cyclohexyl)-acetic acid Ex.5-67 {4-[4-(5-Cyclopropylmethoxycarbonylamino- 3.61 E 409pyridin-2-yl)-phenyl]-cyclohexyl}-acetic acid Ex. 5-68(4-{4-[5-(Tetrahydro-furan-2- 3.35 E 439ylmethoxycarbonylamino)-pyridin-2-yl]- phenyl}-cyclohexyl)-acetic acidEx. 5-69 (4-{4-[5-(Tetrahydro-pyran-2- 3.59 E 453.1ylmethoxycarbonylamino)-pyridin-2-yl]- phenyl}-cyclohexyl)-acetic acidEx. 5-70 (4-{4-[5-(3-Methyl-oxetan-3- 3.36 E 439.1ylmethoxycarbonylamino)-pyridin-2-yl]- phenyl}-cyclohexyl)-acetic acidEx. 5-71 (4-{4-[5-(Tetrahydro-pyran-4- 3.45 E 453.1ylmethoxycarbonylamino)-pyridin-2-yl]- phenyl}-cyclohexyl)-acetic acidEx. 5-72 (4-{4-[5-(2-Methyl-pyridin-3- 3.47 E 460.1ylmethoxycarbonylamino)-pyridin-2-yl]- phenyl}-cyclohexyl)-acetic acidEx. 5-73 [4-(4-{5-[3-(4-Chloro-3-trifluoromethyl- 4.41 E 532.2phenyl)-ureido]-pyridin-2-yl}-phenyl)- cyclohexyl]-acetic acid

Example 5-74(4-{4-[5-(5-Methylsulfanyl-pyridin-2-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid

2-Bromo-5-methylsulfanyl-pyridine (51 mg, 0.25 mmol) and{4-[4-(5-Amino-pyridin-2-yl)-phenyl]-cyclohexyl}-acetic acid methylester (75 mg, 0.25 mmol) were dissolved in 1,4-dioxane (2 mL) in apressure vessel. Pd₂dba₃ (7 mg, 0.008 mmol) and XANTPHOS (6 mg, 0.01mmol) were added, followed by cesium carbonate (163 mg, 0.50 mmol). Themixture was sparged with nitrogen for 10 minutes, then the vessel wassealed and heated at 80° C. for 18 hours. The mixture was partitionedbetween EtOAc and water, then the organic layer was washed with brine,dried with magnesium sulfate, filtered, and concentrated via rotaryevaporation. The crude material was used in the next step withoutfurther purification; MS (M+H)+ 448.3.

The crude(4-{4-[5-(5-Methylsulfanyl-pyridin-2-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid methyl ester was dissolved in THF/MeOH (4:1, 2.5 mL) and to it wasadded aqueous LiOH (4M, 0.5 mL). The mixture was stirred at roomtemperature for 18 hours, then was immediately purified viareverse-phase HPLC to yield the title compound as a white solid: ¹H NMR(400 MHz, DMSO-d6) δ ppm 1.08-1.20 (m, 2H) 1.44-1.57 (P, 2H) 1.84 (m,5H) 2.16 (d, J=6.82 Hz, 2H) 2.50 (m, 1H) 6.91 (d, J=8.59 Hz, 1H) 7.36(d, J=8.34 Hz, 2H) 7.70 (dd, J=8.59, 2.53 Hz, 1H) 7.91 (d, J=8.34 Hz,2H) 7.95 (d, J=8.84 Hz, 1H) 8.21 (d, J=2.27 Hz, 1H) 8.33 (dd, J=9.09,2.53 Hz, 1H) 8.98 (br. s., 1H) 9.64 (br. s., 1H); MS (M+H)+ 434.2.

Example 5-75((4-{4-[5-(5-Trifluoromethyl-[1,3,4]oxadiazol-2-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid)

128 mg of trifluoroacetyl hydrazide was stirred in 3 ml of DMF andtreated with 178 mg of thiocarbonyl diimidazole at room temperature. Itwas stirred for 3 hours and analyzed by LC-MS. The crude reactionmixture was then treated with 330 mg of{4-[4-(5-Amino-pyridin-2-yl)-phenyl]-cyclohexyl}-acetic acid methylester and stirred overnight at room temperature followed by heating at60° C. for 8 hours. The reaction was analyzed by LC-MS which indicatedcomplete consumption of the starting material. This crude reactionmixture was treated with 100 mg of EDCl at 60° C. and stirred overnightat the same temperature. The reaction was then cooled to roomtemperature and diluted with water. The resulting precipitates werecollected by filtration and purified by column chromatography usinghepthane and ethyl acetate as its eluents to afford((4-{4-[5-(5-trifluoromethyl-[1,3,4]oxadiazol-2-ylamino)-pyridin-2-yl]-phenylycyclohexyl)-aceticacid methyl ester. The whole material was taken for the next hydrolysisstep and dissolved in 4 ml of THF and water (1:1 mixture). 80 mg of LiOHwas added and the reaction was stirred at room temperature for 24 hours.LC-MS indicated the reaction was completed. The reaction mixture wasthen neutralized with 6N-HCl and the resulting precipitates weretriturated in hepthane and ethyl acetate 1:1 mixture and collected byfiltration. The creamy filter cake was dried by air in the suctionfunnel to afford the title compound: ¹H-NMR (400 MHz, DMSO-d₆, δ ppm1.17 (br. s., 1H) 1.14 (d, J=12.38 Hz, 2H) 1.49 (d, J=10.36 Hz, 3H) 1.82(br. s., 5H) 2.15 (d, J=6.82 Hz, 2H) 7.31 (d, J=8.59 Hz, 2H) 7.92 (t,J=9.09 Hz, 3H) 8.07 (dd, J=8.72, 2.65 Hz, 1H) 8.67 (d, J=2.53 Hz, 1H);LCMS (M+H)+=447.2.

Alternatively, the methyl ester can be dissolved in THF and treated withaqueous sodium hydroxide (4 equiv). The mixture can then be stirred at50 degrees for 12 hours, at which point water may be added and most ofthe organic solvent may be removed under reduced pressure. Addition ofacetonitrile followed by cooling may yield a precipitate which can beisolated by filtration to afford the title compound as the correspondingsodium salt.

Using analogous procedures to those described above, the followingcompounds may also be prepared:

Example Name LC rt Method (M + H)+ Ex. 5-76(4-{4-[5-(5-Fluoro-pyridin-3-ylamino)-pyridin-2- 11.1 D 406.2yl]-phenyl}-cyclohexyl)-acetic acid Ex. 5-77(4-{4-[5-(6-Isopropoxy-pyridin-3-ylamino)- 1.49 A 446.2pyridin-2-yl]-phenyl}-cyclohexyl)-acetic acid Ex. 5-78(4-{4-[5-(5-Bromo-pyridin-2-ylamino)-pyridin- 1.51 A 468.12-yl]-phenyl}-cyclohexyl)-acetic acid Ex. 5-79(4-{4-[5-(2-Methoxy-pyrimidin-5-ylamino)- 1.21 A 419.1pyridin-2-yl]-phenyl}-cyclohexyl)-acetic acid Ex. 5-80(4-{4-[5-(6-Methylsulfanyl-pyridin-3-ylamino)- 11.2 D 434.3pyridin-2-yl]-phenyl}-cyclohexyl)-acetic acid Ex. 5-81(4-{4-[5-([1,2,4]Triazin-3-ylamino)-pyridin-2- 7.6 D 390.2yl]-phenyl}-cyclohexyl)-acetic acid Ex. 5-82(4-{4-{5-(2-Dimethylamino-pyrimidin-5- 1.3 A 432.2ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)- acetic acid Ex. 5-83(4-{4-[5-(3,5-Difluoro-pyridin-2-ylamino)- 0.87 B 424.1pyridin-2-yl]-phenyl}-cyclohexyl)-acetic acid Ex. 5-84(4-{4-[5-(6-Trifluoromethyl-pyridin-3-ylamino)- 1.72 A 470.2pyridin-2-yl]-phenyl}-cyclohexyl)-acetic acid methyl ester Ex. 5-85(4-{4-[5-(5-Chloro-6-methoxy-pyridin-3- 1.5 A 452.1ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)- acetic acid Ex. 5-86(4-{4-[5-(5-Fluoro-4-methyl-pyridin-2-ylamino)- 0.89 B 420.1pyridin-2-yl]-phenyl}-cyclohexyl)-acetic acid Ex. 5-87(4-{4-[5-(3-Chloro-5-methyl-pyridin-2- 1.62 A 436.2ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)- acetic acid Ex. 5-88(4-{4-[5-(5-Difluoromethyl-6-methoxy-pyridin- 1.41 A 468.13-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)- acetic acid Ex. 5-89(4-{4-[5-(5-Methanesulfonyl-pyridin-2- 1.1 A 466.2ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)- acetic acid Ex. 5-90(4-{4-[3-Fluoro-5-(6-trifluoromethyl-pyridin-3- 1.48 A 474.1ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)- acetic acid Ex. 5-91(4-{4-[5-(1H-Benzoimidazol-2-ylamino)- 10.8 D 427.1pyridin-2-yl]-phenyl}-cyclohexyl)-acetic acid Ex. 5-92(4-{4-{5-(6-Methyl-benzooxazol-2-ylamino)- 4.43 E 442pyridin-2-yl]-phenyl}-cyclohexyl)-acetic acid Ex. 5-93(4-{4-[5-(2-Methyl-5-trifluoromethyl-2H- 1.42 A 459pyrazol-3-ylamino)-pyridin-2-yl]-phenyl}- cyclohexyl)-acetic acid Ex.5-94 (4-{4-[5-(6-Chloro-benzooxazol-2-ylamino)- 15.4 D 476.1pyridin-2-yl]-phenyl}-cyclohexyl)-acetic acid methyl ester Ex. 5-95(4-{4-[5-(6-Chloro-benzooxazol-2-ylamino)- 13.6 D 462pyridin-2-yl]-phenyl}-cyclohexyl)-acetic acid Ex. 5-96(4-{4-[5-(5-Chloro-6-methoxy-benzooxazol-2- 13.4 D 492.2ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)- acetic acid Ex. 5-97(4-{4-[5-(5-tert-Butyl-[1,3,4]oxadiazol-2- 13 D 435ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)- acetic acid

Example 5-98(4-{4-[5-(4-Trifluoromethyl-benzenesulfonylamino)-pyridin-2-yl[-phenyl}-cyclohexyl)-aceticacid

(4-{4-[5-(4-Trifluoromethyl-benzenesulfonylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid methyl ester. To a solution of 0.300 g (0.925 mmol) of{4-[4-(5-Amino-pyridin-2-yl)-phenyl)-cyclohexyl}-acetic acid methylester, and 8 mL of dichloromethane was added 0.112 mL (1.39 mmol) ofpyridine, 0.271 g (1.11 mmol) of 4-Trifluoromethyl-benzenesulfonylchloride and 0.004 g (0.0277 mmol) DMAP. The dark orange solution wasstirred at r.t. for 4 h. The mixture was extracted with dichloromethane,then washed with water, 1N HCl, and brine. Dried with Na₂SO₄. Purifiedon silica gel (EtOAc/Heptane, 9:1 to 6:4) to afford the title compound.1H NMR (400 MHz, CHLOROFORM-d₆) 0.99-1.10 (m, 2H) 1.34-1.46 (m, 2H)1.71-1.82 (m, 5H) 2.14 (d, J=6.82 Hz, 2H) 2.39 (tt, J=12.16, 3.25 Hz,1H) 3.57 (s, 3H) 7.16 (d, J=8.34 Hz, 2H) 7.54 (dd, J=2.53, 1.77 Hz, 2H)7.61 (d, J=8.34 Hz, 2H) 7.73 (d, J=8.34 Hz, 2H) 7.78 (d, J=8.08 Hz, 2H)8.14 (dd, J=2.27, 1.01 Hz, 1H).

(4-{4-[5-(4-Trifluoromethyl-benzenesulfonylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid. To a solution of 0.136 g (0.256 mmol) of(4-{4-[5-(4-Trifluoromethyl-benzenesulfonylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid methyl ester in THF/MeOH (4:1) was added 0.500 mL of LiOH (4 M) andlet stir at r.t. for 72 h. Removed solvent in vacuo. The residue wastaken up in water, brought to pH 4 and the solid filtered to afford thetitle compound. 1H NMR (400 MHz, DMSO-d6) δ ppm. 1.20-1.31 (m, 2H)1.55-1.66 (m, 2H) 1.81-1.89 (m, 1H) 1.92-1.97 (m, 4H) 2.27 (d, J=6.82Hz, 2H) 7.43 (d, J=8.34 Hz, 2H) 7.69 (dd, J=8.59, 2.78 Hz, 1H) 7.97 (d,J=8.59 Hz, 1H) 8.02 (d, J=8.34 Hz, 2H) 8.12 (m, 4H) 8.47 (d, J=0.51 Hz,1H) 10.96 (br. s., 1H) 12.13 (br. s., 1H); (M+H)+=519.1.

Using analogous procedures, the following compounds may also beprepared:

Example Name LC rt Method (M + H)+ Ex. 5-99 (4-{4-[5-(3-Trifluoro- 1.48A 519.2 methyl-benzenesulfonylamino)- pyridin-2-yl]-phenyl}-cyclo-hexyl)-acetic acid Ex. 5-100 (4-{4-[5-(1,2-Dimethyl- 1.07 A 4691H-imidazole-4-sulfonyl- amino)-pyridin-2-yl]-phenyl}-cyclohexyl)-acetic acid

Example 6-1(4-{4-[6-(3-Chloro-phenylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-aceticacid

A. [4-(4-Acetyl-phenyl)-cyclohexyl]-acetic acid ethyl ester

To a 0° C. solution of (4-phenyl-cyclohexyl)-acetic acid ethyl ester (15g, 61 mmol, 1.0 equiv) in 200 Ml DCM was added aluminum trichloride (16g, 122 mmol, 2.0 equiv) portionwise over 15 min. Acetyl chloride (4.7Ml, 67 mmol, 1.10 equiv) was then added dropwise via syringe. Thehomogeneous solution was allowed to stir at 0° C. for 2 h, thencarefully quenched with 300 Ml ice water. The mixture was extracted withDCM (3×150 Ml), and the organic extracts were washed with saturatedbicarbonate and brine solution. Removal of solvent in vacuo afforded thetitle compound: ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.10 (q, J=11.96Hz, 2H) 1.20 (t, J=7.20 Hz, 3H) 1.40-1.51 (m, 2H) 1.84 (d, J=11.12 Hz,4H) 1.76-1.87 (m, 1H) 2.17 (d, J=6.82 Hz, 2H) 2.50 (s, 3H) 4.07 (q,J=7.07 Hz, 2H) 7.22 (d, J=8.34 Hz, 2H) 7.81 (d, J=8.08 Hz, 2H); (M+H)+289.1.

B. {4-[4-(6-Oxo-1,6-dihydro-pyridazin-3-yl)-phenyl]-cyclohexyl}-aceticacid ethyl ester

To a solution of [4-(4-acetyl-phenyl)-cyclohexyl]-acetic acid ethylester (17 g, 59 mmol, 1.0 equiv) in 100 Ml glacial acetic acid was addedglyoxylic acid monohydrate (5.4 g, 59 mmol, 1.0 equiv) as a solid. Thesolution was heated to 100° C. for 2 h. The mixture was then cooled to40° C., then 75 Ml water was added followed by 120 Ml of a 28% ammoniumhydroxide solution until the Ph was measured to be 8. Hydrazine (2.0 Ml,65 mmol, 1.1 equiv) was then added via syringe, and the reaction wasthen heated to 95° C. for 2 hr. Upon cooling to room temperature, asolid precipitate was filtered off to afford the title compound inaddition to the uneliminated product{4-[4-(5-hydroxy-6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-phenyl]-cyclohexyl}-aceticacid ethyl ester. This mixture was taken into the next step withoutfurther purification. (M+H)+ 341.2.

C. {4-[4-(6-Chloro-pyridazin-3-yl)-phenyl]-cyclohexyl}-acetic acid ethylester

A 50 Ml flask was charged with{4-[4-(6-oxo-1,6-dihydro-pyridazin-3-yl)-phenyl]-cyclohexyl}-acetic acidethyl ester (0.76 g, 2.2 mmol, 1.0 equiv) in 20 Ml toluene followed byphosphorous oxychloride (0.62 Ml, 6.7 mmol, 3.0 equiv). The suspensionwas heated to 100° C., at which point a homogeneous solution ensued. Thereaction was stirred overnight at 100° C., then cooled to roomtemperature. Removal of volatiles in vacuo afforded the title compound:1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.07-1.17 (m, 2H) 1.20 (t, J=7.07Hz, 3H) 1.43-1.53 (m, 2H) 1.78-1.90 (m, 5H) 2.18 (d, J=6.57 Hz, 2H)2.44-2.52 (m, 1H) 4.08 (q,J=7.07 Hz, 2H) 7.29 (d, J=8.34 Hz, 2H) 7.46(d, J=9.09 Hz, 1H) 7.72 (d, J=9.09 Hz, 1H) 7.90 (d, J=8.59 Hz, 2H);(M+H)+ 359.

D.(4-{4-[6-(3-Chloro-phenylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-aceticacid ethyl ester

To a suspension of{4-[4-(6-chloro-pyridazin-3-yl)-phenyl]-cyclohexyl)-acetic acid ethylester (2.0 g, 5.6 mmol, 1.0 equiv) in 40 Ml dioxane was added3-chloroaniline (0.70 Ml, 6.7 mmol, 1.2 equiv) followed by 2 Ml 4 N HClin dioxane. The mixture was then heated to 100° C. overnight. Thereaction was partitioned between EtOAc and saturated bicarbonatesolution, and the organic extracts were then washed with brine anddried. Removal of solvent in vacuo afforded the title compound: 1H NMR(400 MHz, CHLOROFORM-d) δ ppm 1.07-1.17 (m, 2H) 1.21 (t, J=7.20 Hz, 3H)1.42-1.53 (m, 2H) 1.86 (t, J=10.99 Hz, 4H) 1.78-1.90 (m, 1H) 2.18 (d,J=6.57 Hz, 2H) 2.47 (td, J=12.00, 3.03 Hz, 1H) 4.08 (q, J=7.24 Hz, 2H)7.03 (d, J=7.58 Hz, 1H) 7.26 (d, J=8.08 Hz, 3H) 7.20-7.28 (m, 2H) 7.45(s, 1H) 7.68 (d, J=9.35 Hz, 1H) 7.84 (d, J=8.34 Hz, 2H); (M+H)+ 450.2.

E.4-{4-[6-(3-Chloro-phenylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-aceticacid

To a solution of(4-{4-[6-(3-chloro-phenylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-aceticacid ethyl ester (1.8 g) in 50 Ml THF/EtOH (4:1) was added 5 Ml of 10%LiOH. The reaction was allowed to stir at 50° C. for 3 h, then stirredovernight at room temperature. Acidification with concentrated HClafforded a precipitate which was recrystallized from EtOH to afford thetitle compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.00-1.10 (m, 2H)1.37-1.48 (m, 2H) 1.61-1.71 (m, 1H) 1.76 (d, J=11.12 Hz, 4H) 2.05 (d,J=6.82 Hz, 2H) 6.92 (ddd, J=7.83, 2.02, 0.76 Hz, 1H) 7.14 (d, J=9.60 Hz,1H) 7.28 (dd, J=8.21, 6.44 Hz, 3H) 7.49 (ddd, J=8.34, 2.02, 0.76 Hz, 1H)7.91 (dd, J=16.55, 8.97 Hz, 3H) 8.10 (t, J=2.02 Hz, 1H) 9.52 (s, 1H);(M+H)+ 422.2.

Alternatively, the methyl ester can be dissolved in THF and treated withaqueous sodium hydroxide (4 equiv). The mixture can then be stirred at50 degrees for 12 hours, at which point water may be added and most ofthe organic solvent may be removed under reduced pressure. Addition ofacetonitrile followed by cooling may yield a precipitate which can beisolated by filtration to afford the title compound as the correspondingsodium salt.

Using the appropriate amine, the following compounds may also beprepared in similar fashion:

MS Example Chemical Name LC rt Method (M + H)⁺ Ex. 6-2(4-{4-[6-(3-Fluoro-phenylamino)- 1.45 A 406.2pyridazin-3-yl]-phenyl}-cyclohexyl)-acetic acid Ex. 6-3{4-[4-(6-m-Tolylamino-pyridazin-3-yl)- 1.35 A 402.2phenyl]-cyclohexyl}-acetic acid Ex. 6-4(4-{4-[6-(3-Trifluoromethyl-phenylamino)- 1.45 A 456.1pyridazin-3-yl]-phenyl}-cyclohexyl)-acetic acid Ex. 6-5(4-{4-[6-(3-Methoxy-phenylamino)- 1.28 A 418.2pyridazin-3-yl]-phenyl}-cyclohexyl)-acetic acid Ex. 6-6(4-{4-[6-(3-Cyano-phenylamino)- 1.21 A 413.2pyridazin-3-yl]-phenyl}-cyclohexyl)-acetic acid Ex. 6-7(4-{4-[6-(2-Fluoro-phenylamino)- 1.23 A 406.3pyridazin-3-yl]-phenyl}-cyclohexyl)-acetic acid Ex. 6-8(4-{4-[6-(4-Chloro-phenylamino)- 1.35 A 422.2pyridazin-3-yl]-phenyl}-cyclohexyl)-acetic acid Ex. 6-9{4-[4-(6-p-Tolylamino-pyridazin-3-yl)- 1.31 A 402.3phenyl]-cyclohexyl}-acetic acid Ex. 6-10(4-{4-[6-(4-Trifluoromethyl-phenylamino)- 1.43 A 456.3pyridazin-3-yl]-phenyl}-cyclohexyl)-acetic acid Ex. 6-11(4-{4-[6-(3-Chloro-4-methoxy- 1.32 A 452.2phenylamino)-pyridazin-3-yl]-phenyl}- cyclohexyl)-acetic acid Ex. 6-12(4-{4-[6-(3-Chloro-2-methyl- 1.38 A 436.2phenylamino)-pyridazin-3-yl]-phenyl}- cyclohexyl)-acetic acid Ex. 6-13{4-[4-(6-Phenylamino-pyridazin-3-yl)- 1.24 A 388.3phenyl]-cyclohexyl}-acetic acid Ex. 6-14 (4-{4-[6-(3-Chloro-2-methoxy-1.38 A 452.3 phenylamino)-pyridazin-3-yl]-phenyl}- cyclohexyl)-aceticacid Ex. 6-15 (4-{4-[6-(2-Methoxy-phenylamino)- 1.28 A 418.3pyridazin-3-yl]-phenyl}-cyclohexyl)-acetic acid Ex. 6-16(4-{4-[6-(4-Methoxy-phenylamino)- 1.26 A 418.3pyridazin-3-yl]-phenyl}-cyclohexyl)-acetic acid Ex. 6-17(4-{4-[6-(6-Trifluoromethyl-pyridin-3- 1.26 A 457.3ylamino)-pyridazin-3-yl]-phenyl}- cyclohexyl)-acetic acid Ex. 6-18(4-{4-[6-(4-Trifluoromethoxy- 1.46 A 472.4phenylamino)-pyridazin-3-yl]-phenyl}- cyclohexyl)-acetic acid Ex. 6-19(4-{4-[6-(4-Fluoro-phenylamino)- 1.34 A 406.2pyridazin-3-yl]-phenyl}-cyclohexyl)-acetic acid Ex. 6-20(4-{4-[6-(6-Amino-pyridin-3-ylamino)- 0.94 A 404.3pyridazin-3-yl]-phenyl}-cyclohexyl)-acetic acid Ex. 6-21(4-{4-[6-(Methyl-m-tolyl-amino)-pyridazin- 1.44 A 416.33-yl]-phenyl}-cyclohexyl)-acetic acid Ex. 6-22[4-(4-6-[(3-Chloro-phenyl)-methyl- 1.46 A 436.1amino]-pyridazin-3-yl}-phenyl)- cyclohexyl]-acetic acid Ex. 6-23[4-(4-{6-[(3-Methoxy-phenyl)-methyl- 1.39 A 432.2amino]-pyridazin-3-yl}-phenyl)- cyclohexyl]-acetic acid Ex. 6-24(4-{4-[6-(2-Methyl-6-trifluoromethyl- 1.36 A 471.1pyridin-3-ylamino)-pyridazin-3-yl]-phenyl}- cyclohexyl)-acetic acid Ex.6-25 (4-{4-[6-(3-Chloro-2-methoxy- 1.38 A 452.3phenylamino)-pyridazin-3-yl]-phenyl}- cyclohexyl)-acetic acid

Example 6-262-{4-[6-(3-Chloro-phenylamino)-pyridazin-3-yl]-benzoylamino}-3-methyl-butyricacid

A. 4-[6-(3-Chloro-phenylamino)-pyridazin-3-yl]-benzoic acid

To a slurry of 4-[6-chloro-pyradazin-3-yl]-benzoic acid (0.30 g, 1.3mmol, 1.0 equiv) in 5 Ml dioxane was added 3-chloroaniline (0.15 Ml, 1.4mmol, 1.1 equiv) followed by 4 M HCl in dioxane (0.34 Ml, 1.4 mmol, 1.0equiv). The suspension was heated to 110° C. for 1 h. The cooledreaction was diluted with DCM, and the resulting precipitate wasfiltered to afford the title compound: ¹H NMR (400 MHz, DMSO-d6) δ 6.90(ddd, J=7.83, 2.02, 0.76 Hz, 1H) 7.13 (d, J=9.35 Hz, 1H) 7.23 (t, J=8.08Hz, 1H) 7.45 (ddd, J=8.34, 2.02, 0.76 Hz, 1H) 7.91-7.95 (m, 2H) 8.00 (d,J=9.35 Hz, 1H) 8.03-8.08 (m, 3H) 9.56 (s, 1H) 12.90 (br. S., 1H); (M+H)+325.9.

B.2-{4-[6-(3-Chloro-phenylamino)-pyridazin-3-yl]-benzoylamino}-3-methyl-butyricacid

To a solution of 4-[6-(3-Chloro-phenylamino)-pyridazin-3-yl]-benzoicacid (0.10 g, 0.31 mmol, 1.0 equiv) in 2 Ml DMF was added HATU (0.23 g,0.62 mmol, 2.0 equiv) and N,N-diisopropylethylamine (0.27 Ml, 1.5 mmol,5.0 equiv). Valine methyl ester (0.062 g, 0.37 mmol, 1.0 equiv) wasadded as a solid, and the homogeneous solution was allowed to stir atroom temperature overnight. To the solution was then added 1 Ml 10%aqueous LiOH, and the mixture was then heated to 55° C. The reactionswere then filtered and the purified by reverse-phase HPLC to afford thetitle compound: ¹H NMR (400 MHz, MeOD) δ 0.96 (dd, J=9.35, 6.82 Hz, 6H)2.21 (dq, J=12.13, 6.82 Hz, 1H) 4.41 (d, J=5.05 Hz, 1H) 6.91 (ddd,J=1.26 Hz, 2.02, 1.01 Hz, 1H) 7.21 (t, J=8.08 Hz, 1H) 7.17 (d, J=9.35Hz, 1H) 7.48 (dd, J=9.22, 1.14 Hz, 1H) 7.88-8.02 (m, 7H); (M+H)+ 425.1.

Using the appropriate amino ester, the following compounds may also beprepared in similar fashion:

MS Example Chemical Name LC rt Method (M + H)⁺ Ex. 6-27(S)-1-{4-[6-(3-Chloro-phenylamino)- 0.98 A 423.0pyridazin-3-yl]-benzoyl}-pyrrolidine-2- carboxylic acid Ex. 6-28(1S,2R)-2-{4-[6-(3-Chloro-phenylamino)- 1.07 A 437.2pyridazin-3-yl]-benzoylamino}- cyclopentanecarboxylic acid Ex. 6-293-{4-[6-(3-Chloro-phenylamino)-pyridazin- 1.05 A 396.93-yl]-benzoylamino)-propionic acid Ex. 6-30(S)-3-{4-[6-(3-Chloro-phenylamino)- 1.21 A 453.2pyridazin-3-yl]-benzoylamino}-5-methyl- hexanoic acid Ex. 6-31(1S,2R)-2-{4-[6-(3-Chloro-phenylamino)- 1.13 A 451.2pyridazin-3-yl]-benzoylamino}- cyclohexanecarboxylic acid Ex. 6-32(S)-1-{4-[6-(3-Chloro-phenylamino)- 1.1 A 436.9pyridazin-3-yl]-benzoyl}-piperidine-2- carboxylic acid

Example 6-332-{4-[6-(3-Chloro-phenylamino)-pyridazin-3-yl]-benzoylamino}-2-methyl-propionicacid

A. 4-(6-Chloro-pyridazin-3-yl)-benzoyl chloride

A suspension of 4-(6-chloro-pyradizin-3-yl)-benzoic acid (2.0 g, 8.5mmol, 1.0 equiv) was suspended in excess thionyl chloride (30 Ml) andheated to reflux overnight. Removal of volatiles in vacuo afforded thetitle compound which was used without further purification: 1H NMR (400MHz, CHLOROFORM-d) δ ppm 7.59 (d, J=8.84 Hz, 1H) 7.85 (d, J=9.09 Hz, 1H)8.15 (d, J=8.00 Hz, 2H) 8.22 (d, J=8.00 Hz, 2H).

B. 2-[4-(6-Chloro-pyridazin-3-yl)-benzoylamino]-2-methyl-propionic acid

A solution of 4-(6-Chloro-pyridazin-3-yl)-benzoyl chloride (0.25 g, 1.0mmol, 1.0 equiv) in 5 Ml THF and 3 Ml DMF was added to a vial containing2-amino isobutyric acid (0.10 g, 1.0 mmol, 1.0 equiv) and 1 N NaOH (2Ml, 2.0 mmol, 2.0 equiv). The homogeneous solution was allowed to stirovernight at room temperature. Acidification to Ph 1 using concentratedHCl afforded a precipitate which was filtered and used directly in thesubsequent step.

C.2-{4-[6-(3-Chloro-phenylamino)-pyridazin-3-yl]-benzoylamino}-2-methyl-propionicacid

A 1-dram vial was charged with 3-chloroaniline (0.2 Ml, excess) and2-[4(6-chloro-pyridazin-3-yl)-benzoylamino]-2-methyl-propionic acid(0.75 g) as a solid. The vial was heated to 100° C. for 1.5 h. The crudereaction mixture was then dissolved in 2 Ml DMF and then purified byreverse-phase preparative HPLC to afford the title compound: 1H NMR (400MHz, DMSO-D6) δ ppm 1.47 (s, 6H), 7.03 (dd, J=7.45, 1.64 Hz, 1H), 7.28(d, J=9.35 Hz, 1H), 7.36 (t, J=8.08 Hz, 1H), 7.56 (dd, J=8.34, 1.26 Hz,1H), 7.99 (d, J=8.59 Hz, 2H), 8.12-8.19 (m, 4H),8.52 (s, 1H), 9.71 (s,1H); (M+H)+ 411.0.

Example 6-344-{4-[6-(3-Trifluoromethyl-phenylamino)-pyridazin-3-yl)-phenyl}-cyclohexanecarboxylicacid

The synthesis of 4-phenyl-cyclohexanecarboxylic acid methyl ester hasbeen reported in WO2004 047755. Starting from4-phenyl-cyclohexanecarboxylic acid methyl ester, the sequence describedfor Ex. 6-1 was followed to afford the title compound as a mixture ofdiastereomers which were separated by reverse-phase preparative HPLC:

Diastereomer 1: ¹H NMR (400 MHz, DMSO-d6) δ 1.20-1.37 (m, 4H) 1.60-1.70(m, 2H) 1.79 (d, J=10.86 Hz, 2H) 2.01-2.15 (m, 1H) 2.33 (m, 1H) 7.03 (d,J=9.35 Hz, 1H) 7.07 (d, J=7.58 Hz, 1H) 7.16 (d, J=8.34 Hz, 2H) 7.34 (t,J=8.21 Hz, 1H) 7.76 (d, J=8.34 Hz, 2H) 7.72 (d, J=7.83 Hz, 1H) 7.83 (d,J=9.35 Hz, 1H) 8.17 (s, 1H) 9.52 (s, 1H)

Diastereomer 2: ¹H NMR (400 MHz, DMSO-d6) δ 1.69-1.80 (m, 4H) 1.80-1.90(m, 2H) 2.25 (m, m 2H) 2.75-2.80 (m, 2H) 7.37-7.47 (m, 4H) 7.69 (t,J=8.21 Hz, 1H) 8.11 (d, J=8.34 Hz, 2H) 8.08 (dd, J=8.46, 1.64 Hz, 1H)8.17 (d, J=9.35 Hz, 1H) 8.52 (s, 1H) 9.86 (s, 1H); (M+H)+ 442.2.

Example 6-352-(4-{4-[6-(3-Chloro-phenylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-acetamide

To a solution of Ex. 6-1 (0.10 g, 0.24 mmol, 1.0 equiv) in 3 Ml DMF wasadded HATU (0.10 g, 0.26 mmol, 1.1 equiv) followed by ammonium hydroxide(0.06 Ml of a 28% aqueous solution). The homogeneous reaction wasallowed to stir at room temperature for 3 h. The reaction was thenpartitioned between EtOAc and water, and the organic extracts werewashed with brine and dried. The crude residue was then purified byreverse-phase preparative. HPLC to afford the title compound: 1H NMR(400 MHz, DMSO-d6) δ ppm 1.06-1.17 (m, 2H) 1.44-1.54 (m, 2H) 1.72-1.77(m, 1H) 1.82 (br. S., 2H) 1.84 (d, J=3.54 Hz, 2H) 1.99 (d, J=6.82 Hz,2H) 2.52-2.57 (m, 1H) 6.71 (br. S., 1H) 7.01 (ddd, J=8.02, 2.08, 0.76Hz, 1H) 7.22 (d, J=9.35 Hz, 1H) 7.33-7.38 (m, 3H) 7.57 (ddd, J=8.34,2.02, 0.76 Hz, 1H) 7.99 (dd, J=17.43, 8.84 Hz, 3H) 8.18 (t, J=2.02 Hz,1H) 9.57 (s, 1H); (M+H)+ 412.3.

Example 6-36(6-{4-[4-(2H-Tetrazol-5-ylmethyl)-cyclohexyl]-phenyl)-pyridazin-3-yl)-(6-trifluoromethyl-pyridin-3-yl)-amine

A.2-(4-{4-[6-(6-Trifluoromethyl-pyridin-3-ylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-acetamide

Using Ex. 6-17 and the procedure described for Ex. 6-35 above, the titlecompound was produced and used in the subsequent step without furtherpurification: (M+H)+ 456.3.

B.(4-{4-[6-(6-Trifluoromethyl-pyridin-3-ylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-acetonitrile

To a mixture of2-(4-{4-[6-(6-Trifluoromethyl-pyridin-3-ylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-acetamide(0.18 g, 0.41 mmol, 1.0 equiv) in 3 Ml THF was added trifluoroaceticanhydride (0.068 Ml, 0.49 mmol, 1.2 equiv) followed by triethylamine(0.12 Ml, 0.90 mmol, 2.2 equiv). The reaction was stirred at ambienttemperature overnight, and then concentrated in vacuo. Purification bysilica gel chromatography (10-50% EtOAc in hexanes) afforded the titlecompound: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.39-1.50 (m, J=12.82, 12.54,12.54, 3.54 Hz, 2H) 1.69-1.80 (m, J=12.88, 12.69, 12.69, 3.41 Hz, 2H)1.86-1.97 (m, J=11.91, 11.91, 6.06, 5.87, 2.91 Hz, 1H) 2.09 (d, J=15.92Hz, 1H) 2.09 (dd, J=5.94, 3.66 Hz, 3H) 2.76 (t, J=3.03 Hz, 1H) 7.53 (d,J=9.35 Hz, 1H) 7.59 (d, J=8.34 Hz, 2H) 8.08 (d, J=8.59 Hz, 1H) 8.20 (d,J=8.34 Hz, 2H) 8.30 (d, J=9.35 Hz, 1H) 8.91 (dd, J=8.59, 2.27 Hz, 1H)9.16 (d, J=2.53 Hz, 1H) 10.25 (s, 1H); (M+H)+ 438.3.

C.(6-{4-[4-(2H-Tetrazol-5-ylmethyl)-cyclohexyl]-phenyl}-pyridazin-3-yl)-(6-trifluoromethyl-pyridin-3-yl)-amine

To a mixture of(4-{4-[6-(6-Trifluoromethyl-pyridin-3-ylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-acetonitrile(0.12 g, 0.29 mmol, 1.0 equiv) in 3 Ml DMF was added sodium azide (0.057g, 0.88 mmol, 3.0 equiv), followed by solid ammonium chloride (0.062 g,4.0 equiv). The reaction was heated to 140° C. over the weekend. Thecooled reaction mixture was diluted with 10 Ml water and then acidifiedto Ph 4-5. The precipitate was filtered to afford the title compound: 1HNMR (400 MHz, DMSO-d6) δ ppm 103-1.16 (m, 2H) 1.33-1.45 (m, 2H) 1.73 (t,J=14.27 Hz, 5H) 2.60-2.68 (m, 3H) 7.27 (dd, J=17.94, 8.84 Hz, 3H) 7.79(d,J=8.84 Hz, 1H) 7.86-7.95 (m, 2H) 8.01 (d, J=9.09 Hz, 1H) 8.63 (dd,J=8.59, 1.77 Hz, 1H) 8.87 (d, J=2.27 Hz, 1H) 9.99 (s, 1H); (M+H)+ 481.7.

Example 6-373-(4-{4-[6-(6-Trifluoromethyl-pyridin-3-ylamino)-pyridazin-3-yl]-phenyl}-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one

A.N-Hydroxy-2-(4-{4-[6-(6-trifluoromethyl-pyridin-3-ylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-acetamidine

To a solution of(4-{4-[6-(6-Trifluoromethyl-pyridin-3-ylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-acetonitrile(0.15 g, 0.34 mmol, 1.0 equiv) in 4 Ml DMSO was added hydroxylaminehydrochloride (0.12 g, 1.7 mmol, 5.0 equiv) and triethylamine (0.25 Ml,1.8 mmol, 5.2 equiv). The yellow solution was heated to 120° C. usingmicrowave heating for 10 min. Additional portions of hydroxylaminehydrochloride and triethylamine were added, and the reaction was allowedto stir overnight at 75° C. The reaction was partitioned between EtOAcand water, and the organic extracts were washed with saturated NaHCO3followed by brine. The organic layer was then dried over sodiumsulphate, filtered, and concentrated in vacuo to afford the titlecompound which was used without further purification: (M+H)+ 471.2.

B.[1-[(Z)-Hydroxyimino]-2-(4-{4-[6-(6-trifluoromethyl-pyridin-3-ylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-ethyl]-carbamicacid isobutyl ester

To a solution ofN-Hydroxy-2-(4-{4-[6-(6-trifluoromethyl-pyridin-3-ylamino)-pyridazin-3-yl)-phenyl}-cyclohexyl)-acetamidine(0.13 g, 0.28 mmol, 1.0 equiv) in 2 Ml DMF was added pyridine (0.023 Ml,0.31 mmol, 1:1 equiv). The solution was cooled to 0° C., then isobutylchloroformate (0.04 Ml, 0.31 mmol, 1.1 equiv) was added dropwise viasyringe. The reaction was allowed to warm to room temperature andstirred for 2 h. Extractive aqueous workup afforded the title compoundwhich was used in the next step without further purification. (M+H)+571.4.

C.3-(4-{4-[6-(6-Trifluoromethyl-pyridin-3-ylamino)-pyridazin-3-yl]-phenyl}-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one

A solution of[1-[(Z)-hydroxyimino]-2-(4-{4-[6-(6-trifluoromethyl-pyridin-3-ylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-ethyl]-carbamicacid isobutyl ester (0.13 g, 0.23 mmol; 1.0 equiv) was dissolved in am-xylene/THF (4:1) mixture and then heated to 180° C. for 20 min. Thecooled reaction was partitioned between EtOAc and water, and the organiclayers were washed with brine and dried. Purification by silica gelchromatography (10-100% MeOH in DCM) afforded the title compound: 1H NMR(400 MHz, DMSO-d6) δ ppm 0.99-1.10 (m, 2H) 1.34 (q, J=11.79 Hz, 2H) 1.59(ddd, J=11.12, 7.58, 4.04 Hz, 1H) 1.70 (t, J=14.02 Hz, 4H) 2.29 (d,J=6.82 Hz, 2H) 2.38-2.46 (m, 1H) 7.23 (d, J=8.08 Hz, 2H) 7.18 (d, J=9.35Hz, 1H) 7.72 (d, J=8.59 Hz, 1H) 7.84 (d, J=8.08 Hz, 2H) 7.94 (d, J=9.35Hz, 1H) 8.56 (dd, J=8.59, 1.26 Hz, 1H) 8.81 (d, J=1.77 Hz, 1H) 9.90 (s,1H) 12.03 (br. S., 1H); (M+H)+ 497.2.

Example 6-38(1-{4-[6-(3-Trifluoromethyl-phenylamino)-pyridazin-3-yl]-phenyl}-piperidin-4-yl)-aceticacid

A. [1-(4-Acetyl-phenyl)-piperidin-4-yl]-acetic acid ethyl ester

A microwave vial was charged with 4′-fluoroacetophenone (1.2 Ml, 10.4mmol, 1.0 equiv) and 2-(piperidin-4-yl)-acetic acid ethyl ester (3.5 g,20.7 mmol, 2.0 equiv) in 20 Ml DMSO. The homogeneous reaction was heatedto 150° C. for 20 min. The cooled reaction was then diluted with etherand washed sequentially with saturated ammonium chloride, water, andbrine. The organic extracts were then dried over sodium sulphate,filtered, and concentrated in vacuo. Purification by flashchromatography (10-40% EtOAc in hexanes) afforded the title compound: 1HNMR (400 MHz, CHLOROFORM-d) δ ppm 1.32 (t, J=7.07 Hz, 3H) 1.47 (d,J=12.13 Hz, 2H) 1.62 (br.s., 1H) 1.90 (d, J=12.63 Hz, 2H) 2.04-2.15 (m,J=11.18, 11.18, 7.45, 7.45, 3.79, 3.66 Hz, 1H) 2.33 (d,J=7.07 Hz, 2H)2.57 (s, 3H) 2.97 (td, J=12.57, 2.15 Hz, 2H) 3.93 (d, J=12.88 Hz, 2H)4.20 (q, J=7.07 Hz, 2H) 6.96 (d, J=6.82 Hz, 2H) 7.92 (d, J=9.09 Hz, 2H);(M+H)+ 290.1.

B.(1-{4-[6-(3-Trifluoromethyl-phenylamino)-pyridazin-3-yl]-phenyl}-piperidin-4-yl)-aceticacid

Starting from [1-(4-Acetyl-phenyl)-piperidin-4-yl]-acetic acid ethylester, steps B-D from Ex. 6-1 were followed using 3-trifluoromethylaniline to afford the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm1.30 (td, J=11.94, 8.72 Hz, 2H) 1.79 (br. S., 1H) 1.76 (d, J=2.78 Hz,1H) 1.86 (td, J=11.05, 4.17 Hz, 1H) 2.20 (d, J=6.82 Hz, 2H) 2.77 (t,J=11.37 Hz, 2H) 3.82 (d, J=12.63 Hz, 2H) 7.04 (d, J=8.84 Hz, 2H) 7.20(d, J=9.35 Hz, 1H) 7.28 (d, J=7.83 Hz, 1H) 7.55 (t, J=7.96 Hz, 1H)7.90-8.00 (m, 2H) 7.92 (d, J=8.84 Hz, 2H) 8.40 (s, 1H) 9.63 (s, 1H)12.10 (br. S., 1H); (M+H)+ 457.3.

Example 6-39(4-{4-[4-Methyl-6-(6-trifluoromethyl-pyridin-3-ylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-aceticacid

A. [4-(4-Propionyl-phenyl)-cyclohexyl]-acetic acid ethyl ester

Using proprionyl chloride in step A for Ex. 6-1, the title compound wassynthesized in analogous fashion: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm1.11-1.22 (m, 8H) 1.40-1.51 (m, 2H) 1.84 (d, J=10.11 Hz, 4H) 2.10 (s,1H) 2.17 (d, J=6.82 Hz, 2H) 2.41-2.51 (m, 1H) 2.90 (q, J=7.16 Hz, 2H)4.08 (q, J=7.07 Hz, 2H) 7.21 (d, J=8.34 Hz, 2H) 7.82 (d, J=8.34 Hz, 2H).

B.(4-{4-[4-Methyl-6-(6-trifluoromethyl-pyridin-3-ylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-aceticacid

Starting from (4-(4-Propionyl-phenyl)-cyclohexyl]-acetic acid ethylester, steps B-D from Ex. 6-1 were followed using6-trifluoromethyl-pyridin-3-ylamine to afford the title compound: 1H NMR(400 MHz, DMSO-d6) δ ppm 1.04-1.15 (m, 2H) 1.48 (m, 2H) 1.74 (m,J=10.99, 4.17 Hz, 1H) 1.85 (d, J=11.12 Hz, 4H) 1.99 (d, J=6.32 Hz, 2H)2.30 (s, 3H) 7.20 (s, 1H) 7.34 (d, J=8.08 Hz, 2H) 7.49 (d, J=8.34 Hz,2H) 7.84 (d, J=8.84 Hz, 1H) 8.67 (dd, J=8.59, 2.27 Hz, 1H) 8.98 (d,J=2.27 Hz, 1H) 10.27 (s, 1H); (M+H)+ 471.2.

Example 6-40(4-{4-[4-Methyl-6-(4-trifluoromethyl-phenylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-aceticacid

The title compound was prepared in analogous fashion using4-trifluoromethyl aniline: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10-1.21 (m,2H) 1.47-1.58 (m, 2H) 1.71-1.80 (m, 1H) 1.86 (d, J=10.11 Hz, 4H) 2.16(d, J=6.82 Hz, 2H) 2.29 (s, 3H) 2.56 (m, 1H) 7.11 (s, 1H) 7.35 (d,J=8.34 Hz, 2H) 7.51 (d, J=8.08 Hz, 2H) 7.66 (d, J=8.59 Hz, 2H)7.99 (d,J=8.59 Hz, 2H) 9.67 (s, 1H) 12.01 (s, 1H); (M+H)+ 470.2.

Example 7(4-{4-[5-(6-Trifluoromethyl-pyridin-3-ylamino)-pyrazin-2-yl]-phenyl}-cyclohexyl)-aceticacid

A. Pyrazin-2-yl-(6-trifluoromethyl-pyridin-3-yl)-amine

To a solution of 5-amino-2-trifluoromethylpyridine (0.81 g) in 3 Mltoluene was added chloropyrazine (0.45 Ml, 1.0 equiv) via syringe. Thehomogeneous solution was heated to 95° C., then cooled to roomtemperature and concentrated in vacuo. Purification by silica gelchromatography (40% EtOAc in hexanes) afforded the title compound: 1HNMR (400 MHz, CHLOROFORM-D) δ ppm 7.5 (s, 1H) 7.6 (s, 1H) 8.0 (s, 1H)8.2 (s, 1H) 8.4 (s, 2H) 8.8 (s, 1H); (M+H)+ 241.1.

B. (5-Bromo-pyrazin-2-yl)-(6-trifluoromethyl-pyridin-3-yl)-amine

A solution of pyrazin-2-yl-(6-trifluoromethyl-pyridin-3-yl)-amine (0.47g) was dissolved in 50 Ml MeOH and then charged with N-bromosuccinimide(0.35 g) in a single portion as a solid. The reaction was stirredovernight at room temperature, then concentrated in vacuo. Purificationby silica gel chromatography (25% EtOAc in hexanes) afforded the titlecompound: 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 6.7 (s, 1H) 7.5 (s, 1H)7.9 (s, 1H) 8.2 (s, 2H) 8.6 (s, 1H); (M+H)+ 320.9.

C.(4-{4-[5-(6-Trifluoromethyl-pyridin-3-ylamino)-pyrazin-2-yl]-phenyl}-cyclohexyl)-aceticacid methyl ester

A solution of(5-Bromo-pyrazin-2-yl)-(6-trifluoromethyl-pyridin-3-yl)-amine (0.072 g)and {4-[4-(5-bromo-pyridin-2-yl)-phenyl]-cyclohexyl}-acetic acid methylester (0.087 g) in 2 Ml DME was charged with 2 M sodium carbonate (1 Ml)and Pd(PPh3)4 (0.027 g, 0.1 equiv). The biphasic mixture was spargedwith nitrogen for 3 min, then stirred at 130° C. under microwave heatingfor 30 min. The reaction was partitioned between EtOAc and water, andthe organic extracts were dried over magnesium sulphate and concentratedin vacuo. Purification by silica gel chromatography (33% EtOAc inhexanes) afforded the title compound: (M+H)+ 471.2.

D.(4-{4-[5-(6-Trifluoromethyl-pyridin-3-ylamino)-pyrazin-2-yl]-phenyl}-cyclohexyl)-aceticacid

To a solution of(4-{4-[5-(6-trifluoromethyl-pyridin-3-ylamino)-pyrazin-2-yl]-phenyl}-cyclohexyl)-aceticacid methyl ester (0.051 g) in 4 Ml THF/water (1:1) was added solidlithium hydroxide (0.030 g). The reaction was stirred at roomtemperature for 48 h, then heated to 45° C. for 24 h. The reaction wasneutralized with 6 N hydrochloric acid and then purified byreverse-phase preparative HPLC to afford the title compound: 1H NMR (400MHz, DMSO-D6) δ ppm 1.1 (s, 2H) 1.3 (s, 1H) 1.6 (s, 2H) 1.9 (s, 6H) 3.5(s, 6H) 7.4 (s, 2H) 7.9 (s, 1H) 8.0 (s, 2H) 8.6 (s, 1H), 8.6 (s, 1H) 8.9(s, 1H) 9.1 (s, 1H) 10.9 (s, 1H); (M+H)+ 457.1.

Alternatively, the methyl ester can be dissolved in THF and treated withaqueous sodium hydroxide (4 equiv). The mixture can then be stirred at50 degrees for 12 hours, at which point water may be added and most ofthe organic solvent may be removed under reduced pressure. Addition ofacetonitrile followed by cooling may yield a precipitate which can beisolated by filtration to afford the title compound as the correspondingsodium salt.

Example 8-1(4-{4-[5-(6-Trifluoromethyl-pyridin-3-ylcarbamoyl)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid

6-Trifluoromethyl-pyridin-3-ylamine (963 mg, 6 mmol) was dissolved inDCM (50 mL) 6-Bromo-nicotinic acid (1 g, 5 mmol) andN-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.9 g, 10mmol) were added. Stirred overnight, evaporated to dryness and purifiedby passing over small plug of silica gel eluting with 30% ethyl acetatein hexanes to afford6-Bromo-N-(6-trifluoromethyl-pyridin-3-yl)-nicotinamide: M+1=347.3. 1HNMR (400 MHz, DMSO-D6) δ ppm 7.91 (dd, J=19.83, 8.46 Hz, 2H) 8.26 (dd,J=8.34, 2.53 Hz, 1H) 8.46 (dd, J=8.34, 2.27 Hz, 1H) 8.95 (d, J=2.53 Hz,1H) 9.06 (d, J=2.27 Hz, 1H) 11.00 (s, 1H).

To 200 mg (1 mmol)6-Bromo-N-(6-trifluoromethyl-pyridin-3-yl)-nicotinamide, 217 mg (1 mmol){4-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclohexyl}-aceticacid methyl ester in DME (20 mL), Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (37 mg, 5 mol %), andsaturated sodium carbonate aqueous solution (2 mL) were added and themixture stirred at 80° C. over night under N₂. Evaporated to dryness andpurified by passing over small plug of silica gel (30% ethyl acetate inhexanes) to afford(4-{4-[5-(6-Trifluoromethyl-pyridin-3-ylcarbamoyl)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid methyl ester: M+1=498.1. ¹H NMR (400 MHz, DMSO-D6) δ ppm 1.06 (s,4H) 1.12-1.20 (m, 2H) 1.45-1.57 (m, 2H) 1.81 (d,J=8.59 Hz, 4H) 2.25 (d,J=6.57 Hz, 2H) 2.50-2.57 (m, 1H) 3.60 (s, 2H) 7.39 (d, J=8.34 Hz, 2H)7.94 (d,J=8.84 Hz, 1H) 8.07-8.15 (m, 2H) 8.35-8.43 (m, 1H) 8.50 (d,J=8.59 Hz, 1H) 9.10 (s, 1H) 9.20 (d, J=2.02 Hz, 1H).

To 60 mg (0.1 mmol)(4-{4-[5-(6-Trifluoromethyl-pyridin-3-ylcarbamoyl)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid methyl ester in THF/H₂O (10 mL; 4:1), 5 mL (4M) aqueous LithiumHydroxide solution was added and the mixture stirred at 60° C. for 5hours. Acidified with concentrated hydrochloric acid which precipitatedthe desired compound. Filtered and dried under vacuum to afford(4-{4-[5-(6-Trifluoromethyl-pyridin-3-ylcarbamoyl)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid, which was subsequently dissolved in methanol (5 mL) one equivalentof potassium hydroxide and 2 mL of H₂O were added and the resultingmixture was stirred at 40 C for 2 hours. Evaporated to dryness to afford(4-{4-[5-(6-Trifluoromethyl-pyridin-3-ylcarbamoyl)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid as the potassium salt: M+1=484.1. HRMS=484.1822. ¹H NMR (400 MHz,MeOD) δ ppm 0.79 (d, J=7.33 Hz, 1H) 1.11 (td, J=12.44, 2.91 Hz, 3H)1.43-1.55(m, 2H) 1.67-1.78 (m, J=7.14, 7.14, 6.95, 6.57 Hz, 2H)1.79-1.89 (m, 3H) 2.02 (d, J=7.33 Hz, 2H) 2.14(t, J=7.33 Hz, 1H) 2.47(s, 1H) 7.29 (d, J=8.34 Hz, 2H) 7.75 (d, J=8.59 Hz, 1H) 7.88-7.95 (m,2H) 8.31(dd, J=8.46, 2.40 Hz, 1H) 8.43 (dd, J=8.46, 2.15 Hz, 1H) 8.97(d, J=2.27 Hz, 1H) 9.08 (d, J=1.52 Hz, 1H)

Alternatively, the methyl ester can be dissolved in THF and treated withaqueous sodium hydroxide (4 equiv). The mixture can then be stirred at50 degrees for 12 hours, at which point water may be added and most ofthe organic solvent may be removed under reduced pressure. Addition ofacetonitrile followed by cooling may yield a precipitate which can beisolated by filtration to afford the title compound as the correspondingsodium salt.

Following analogous procedures, the following compounds may also beprepared:

Example Name LC rt Method (M + H)+ Ex. 8-2 {4-[4-(5-Isopropyl- 1.19 A381.1 carbamoyl-pyridin-2-yl)- phenyl]-cyclohexyl}- acetic acid Ex. 8-3{4-[4-(6-Carbamoyl- 1.13 A 338.8 pyridin-2-yl)-phenyl]-cyclohexyl}-acetic acid Ex. 8-4 {4-[4-(6-Isopropyl- 1.18 A 380.9carbamoyl-pyridin-2-yl)- phenyl]-cyclohexyl}- acetic add

The present invention also covers any salts of the hereinabove describedexamples. In particular, the potassium, sodium, hydrochloric,methansulfonic, phosphoric, sufuric acids salts, tert-butyl amine, anddiethylamine. The salts can be prepared by the herein described methods.

1-37. (canceled)
 38. A compound as represented by figure “B”:

or a pharmaceutically acceptable salt thereof wherein: A is asubstituted or unsubstituted alkyl, cycloalkyl, aryl, or heterocyclylgroup, L1 is selected from the group consisting of: an amine group —NH—a substituted amine group of the formula —N(CH₃)—, —CH₂—NH— or—CH₂—CH₂—NH—, an amide group —C(O)—NH—, a sulphonamide group —S(O)₂—NH—,or a urea group —NHC(O)—NH—, B is a substituted or unsubstituted,monocyclic, 5- or 6-membered divalent heteroaryl group, C is asubstituted or unsubstituted divalent phenyl group, L2 is selected fromthe group consisting of: a single bond, a divalent residue having thefollowing structure:—[R^(1l ]) _(a)—[R²]_(b)—[C(O)]_(c)—[N(R³)]_(d)—[R⁴]_(e)—[R⁵]_(f)—wherein a is 0 or 1, b is 0 or 1, c is 0 or 1, d is 0 or 1, e is 0 or 1,f is 0 or 1, with the proviso that (a+b+c+d+e+f)>0, and c=1 if d=1, R¹,R², R⁴ and R⁵, which can be the same or different, are a substituted orunsubstituted divalent alkyl, cycloalkyl, alkenyl, alkynyl, alkylene,aryl or heterocyclyl residue, R³ is H or hydrocarbyl, or R³ and R⁴ formtogether with the nitrogen atom to which they are attached a 5- or6-membered heterocycloalkyl group, with the proviso that R¹ and R² arenot both alkyl if c=1 and d=e=f=0 and the carbonyl carbon atom isattached to the moiety E, an alkylidenyl group which is linked to themoiety D via a double bond, and E is selected from the group consistingof: a sulphonic acid group and derivatives thereof, a carboxyl group andderivatives thereof, wherein the carboxyl carbon atom is attached to L2,a phosphonic acid group and derivatives thereof, an alpha-ketohydroxyalkyl group, a hydroxyalkyl group wherein the carbon atom bondedto the hydroxyl group is further substituted with one or twotrifluoro-methyl groups, a substituted or unsubstituted five-memberedheterocyclyl residue having in the ring at least two heteroatoms and atleast one carbon atom, wherein the at least one carbon atom of the ringis bonded to two heteroatoms; at least one of the heteroatoms to whichthe carbon atom of the ring is bonded is a member of the ring; and atleast one of the heteroatoms to which the carbon atom of the ring isbonded or at least one of the heteroatoms of the ring is bearing ahydrogen atom; with the provisos that E is not a carboxamide group if L2comprises an amide group, L2 is not a divalent N-methyl piperidinylgroup if the moiety E is a pyridinyl-1,2,4-triazolyl group.
 39. Thecompound according to claim 38, wherein the divalent residue—[R¹]_(a)—[R²]_(b)—[C(O)]_(c)—[N(R³)]_(d)—[R⁴]_(e)—[R⁵]_(f)— is selectedfrom the group consisting of: a divalent alkyl group having from 1 to 4carbon atoms a divalent alkenyl group having from 2 to 3 carbon atoms a—C(O)— group a —C(O)—[R⁴]—R⁵— group wherein e is 0 and R⁵ is selectedfrom the group consisting of a divalent substituted or unsubstitutedC₁-C₄ alkyl group, C₄-C₈ cycloalkyl group, phenyl group or 5- or6-membered heterocyclyl group, or e is 1, R⁴ is a divalent substitutedor unsubstituted C₁-C₄ alkyl group, and R⁵ is a divalent substituted orunsubstituted C₄-C₈ cycloalkyl cycloalkyl group, phenyl group or 5- or6-membered heterocyclyl group, a —R¹—R²— group, wherein R¹ is a divalentsubstituted or unsubstituted C₁-C₄ alkyl group and R² is a divalentsubstituted or unsubstituted C₄-C₈ cycloalkyl group, phenyl group or 5-or 6-membered heterocyclyl group, a —C(O)—NH— group, a—(CH₂)₁₋₃—C(O)—NH—(CH₂)₁₋₃— group, a —C(O)—NH—R⁴— group, wherein R⁴ isselected from a divalent substituted or unsubstituted C₁₋₇ alkyl group,cyclohexyl group or cyclopentyl group, a —C(O)—N(R³)—R⁴— group, whereinR³ and R⁴ and the N-atom together form a pyrrolidine ring or apiperidine ring, or a pharmaceutically acceptable salt thereof.
 40. Thecompound according to claim 38, wherein the alkylidenyl group is ═CH—,or a pharmaceutically acceptable salt thereof.
 41. The compoundaccording to claim 38, wherein the L1 group is an amine group —NH—, or apharmaceutically acceptable salt thereof.
 42. The compound according toclaim 38, wherein the L1 group is an amide group —C(O)NH— or —NHC(O)—,or a pharmaceutically acceptable salt thereof.
 43. The compoundaccording to claim 38, wherein the carboxyl group or the derivativethereof representing the moiety E is selected from the group consistingof: a COOH group, a carboxylic ester group, a carboxamide group, or apharmaceutically acceptable salt thereof.
 44. The compound according toclaim 38, wherein the sulphonic acid group or the derivative thereofrepresenting moiety E is selected from the group consisting of: a—S(O)₂—OH group, a —S(O)₂—NHR⁶ group, wherein R⁶ is selected fromhydrogen, a C₁-C₈ alkyl group, a cycloalkyl group, a substituted orunsubstituted aryl group, a substituted or unsubstituted heterocyclylgroup, or a carboxylic acid ester group, or a pharmaceuticallyacceptable salt thereof.
 45. The compound according to claim 38, whereinthe 5-membered heterocyclyl residue representing moiety E is selectedfrom the group consisting of: a tetrazole residue, a triazole residue,an oxadiazole residue, a thiadiazole residue, a diazole residue, anoxazole residue, a thiazole residue, an oxathiadiazole residue, theheterocyclyl residue optionally having one or more substituents selectedfrom an oxo group, a hydroxyl group and/or a thiol group, or apharmaceutically acceptable salt thereof.
 46. The compound according toclaim 38 of formula:

wherein: B is selected from the group consisting of substituted orunsubstituted pyridine, substituted or unsubstituted pyridazine,substituted or unsubstituted pyrimidine, substituted or unsubstitutedpyrazine, and substituted or unsubstituted oxazole, L1 is selected fromthe group consisting of —NH—, —C(O)NH— and —NHC(O)—, A is substituted orunsubstituted cycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heterocyclyl group, L2- is a divalentresidue:—[R¹]_(a)—[R²]_(b)—[C(O)]_(c)—[N(R³)]_(d)—[R⁴]_(e)—[R⁵]— selected fromthe group consisting of: a divalent alkyl group having from 1 to 4carbon atoms a divalent alkenyl group having from 2 to 3 carbon atoms—C(O)— —C(O)—[R⁴]_(e)—R⁵—, wherein e is 0 and R⁵ is selected from thegroup consisting of a divalent substituted or unsubstituted C₁-C₄ alkylgroup, C₄-C₈ cycloalkyl group, phenyl group or 5- or 6-memberedheterocyclyl group, or e is 1, R⁴ is a divalent substituted orunsubstituted C₁-C₄ alkyl group, and R⁵ is a divalent substituted orunsubstituted C₄-C₈ cycloalkyl cycloalkyl group, phenyl group or 5- or6-membered heterocyclyl group, —R¹—R²—, wherein R¹ is a divalentsubstituted or unsubstituted C₁-C₄ alkyl group and R² is a divalentsubstituted or unsubstituted C₄-C₈ cycloalkyl group, phenyl group or 5-or 6-membered heterocyclyl group, —C(O)—NH—,—(CH₂)₁₋₃—C(O)—NH—(CH₂)₁₋₃—, —C(O)—NH—R⁴—, wherein R⁴ is selected from adivalent substituted or unsubstituted C₁₋₇ alkyl group, cyclohexyl groupor cyclopentyl group, —C(O)—N(R³)—R⁴—, wherein R³ and R⁴ and the N-atomtogether form a pyrrolidine ring or a piperidine ring, E is selectedfrom the group consiting of: COOH, a carbocylic ester, a carboxamide,—S(O)₂—OH, —S(O)₂—NHR⁶, wherein R⁶ is selected from hydrogen, a C₁-C₈alkyl group, a cycloalkyl group, a substituted or unsubstituted arylgroup, a substituted or unsubstituted heterocyclyl group, or acarboxylic acid ester group, or a pharmaceutically acceptable saltthereof.
 47. The compound of Formula I:

A is substituted or unsubstituted cycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heterocyclyl, E′ is-L2-E, -L2- is a divalent residue:—[R¹]_(a)—[R²]_(b)—[C(O)]_(c)—[N(R³)]_(d)—[R⁴]_(e)—[R⁵]— selected fromthe group consisting of: a divalent alkyl group having from 1 to 4carbon atoms a divalent alkenyl group having from 2 to 3 carbon atoms—C(O)—, —C(O)—[R⁴]_(e)—R⁵—, wherein e is 0 and R⁵ is selected from thegroup consisting of a divalent substituted or unsubstituted C₁-C₄ alkylgroup, C₄-C₈ cycloalkyl group, phenyl group or 5- or 6-memberedheterocyclyl group, or e is 1, R⁴ is a divalent substituted orunsubstituted C₁-C₄ alkyl group, and R⁵ is a divalent substituted orunsubstituted C₄-C₈ cycloalkyl cycloalkyl group, phenyl group or 5- or6-membered heterocyclyl group, —R¹—R²—, wherein R¹ is a divalentsubstituted or unsubstituted C₁-C₄ alkyl group and R² is a divalentsubstituted or unsubstituted C₄-C₈ cycloalkyl group, phenyl group or 5-or 6-membered heterocyclyl group, —C(O)—N—,—(CH₂)_(1,3)—C(O)—NH—(CH₂)₁₋₃—, —C(O)—NH—R⁴—, wherein R⁴ is selectedfrom a divalent substituted or unsubstituted C₁₋₇ alkyl group,cyclohexyl group or cyclopentyl group, —C(O)—N(R³)—R⁴—, wherein R³ andR⁴ and the N-atom together form a pyrrolidine ring or a piperidine ring,E is selected from the group consisting of: COOH, a carbocylic ester, acarboxamide, —S(O)₂—OH, —S(O)₂—NHR⁶, wherein R⁶ is selected fromhydrogen, a C₁-C₈ alkyl group, a cycloalkyl group, a substituted orunsubstituted aryl group, a substituted or unsubstituted heterocyclylgroup, or a carboxylic acid ester group, or pharmaceutically acceptablesalts, prodrugs, stereoisomers, crystalline forms, or polymorphsthereof.
 48. The compound according to claim 47 of Formula II:

A is substituted or unsubstituted cycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heterocyclyl, E′ is-L2-E, -L2- is a divalent residue:—[R¹]_(a)—[R²]_(b)—[C(O)]_(c)—[N(R³)]_(d)—[R⁴]_(e)—[R⁵]_(f)— selectedfrom the group consisting of: a divalent alkyl group having from 1 to 4carbon atoms a divalent alkenyl group having from 2 to 3 carbon atoms—C(O)—, —C(O)—[R⁴]_(e)—R⁵—, wherein e is 0 and R⁵ is selected from thegroup consisting of a divalent substituted or unsubstituted C₁-C₄ alkylgroup, C₄-C₈ cycloalkyl group, phenyl group or 5- or 6-memberedheterocyclyl group, or e is 1, R⁴ is a divalent substituted orunsubstituted C₁-C₄ alkyl group, and R⁵ is a divalent substituted orunsubstituted C₄-C₈ cycloalkyl cycloalkyl group, phenyl group or 5- or6-membered heterocyclyl group, —R¹—R²—, wherein R¹ is a divalentsubstituted or unsubstituted C₁-C₄ alkyl group and R² is a divalentsubstituted or unsubstituted C₄-C₈ cycloalkyl group, phenyl group or 5-or 6-membered heterocyclyl group, —C(O)—NH—,—(CH₂)₁₋₃—C(O)—NH—(CH₂)₁₋₃—, —C(O)—NH—R⁴—, wherein R⁴ is selected from adivalent substituted or unsubstituted C₁₋₇ alkyl group, cyclohexyl groupor cyclopentyl group, —C(O)—N(R³)—R⁴—, wherein R³ and R⁴ and the N-atomtogether form a pyrrolidine ring or a piperidine ring, E is selectedfrom the group consisting of: COOH, a carbocylic ester, a carboxamide,—S(O)₂—OH, —S(O)₂—NHR⁶, wherein R⁶ is selected from hydrogen, a C₁-C₈alkyl group, a cycloalkyl group, a substituted or unsubstituted arylgroup, a substituted or unsubstituted heterocyclyl group, or acarboxylic acid ester group, or pharmaceutically acceptable salts,prodrugs, stereoisomers, crystalline forms, or polymorphs thereof. 49.The compound of claim 47, wherein A is selected from substituted orunsubstituted phenyl, substituted or unsubstituted pyridine, substitutedor unsubstituted cyclohexyl, substituted or unsubstituted isoxazole,substituted or unsubstituted oxadiazole, or substituted or unsubstitutedpyrazole, and a pharmaceutically acceptable salt thereof.
 50. Thecompound of claim 47, wherein E′ is —C(O)OH, —CH₂—C(O)OH, —CH₂—heterocyclyl, or a pharmaceutically acceptable salt thereof.
 51. Thecompound of claim 38, selected from the group consisting of:(4-{4-[2-(3-Fluorophenylamino)-pyrimidin-5-yl]-phenyl}-cyclohexylyaceticacid, {4-[4-(2-Phenylaminopyrimidin-5-yl)phenyl]-cyclohexyl}-aceticacid,(4-{4-[2-(3-Methoxyphenylamino)-thiazol-4-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[2-(3-Fluorophenylamino)-thiazol-4-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[2-(2-Chlorophenylamino)-thiazol-4-yl]phenyl}-cyclohexyl)-aceticacid,(4-{4-[2-(3-Cyanophenylamino)-thiazol-4-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[2-(3-Trifluoromethylphenylamino)-thiazol-4-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[2-(3-Fluorophenylamino)-thiazol-4-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4′-[2-(3-Chloro-phenylamino)-oxazol-5-yl]-biphenyl-4-yl}-cyclohexyl)-aceticacid,(4-{4-[6-(3-Chloro-phenylamino)-pyridin-3-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[6-(3-methylphenylamino)-pyridin-3-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[6-(3-Trifluoromethylphenylamino)-pyridin-3-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[6-(3-Methoxyphenylamino)-pyridin-3-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[6-(2-Fluorophenylamino)-pyridin-3-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[6-(2-Methoxyphenylamino)-pyridin-3-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[6-(2-Methoxyphenylamino)-pyridin-3-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[5-(6-Trifluoromethyl-pyridin-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[5-(Pyridin-2-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid, {4-[4-(5-Phenylaminopyridin-2-yl)-phenyl]-cyclohexyl}-acetic acid,(4-{4-[5-(5-Cyanopyridin-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[5-(5-Trifluoromethylpyridin-2-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[5-(4-Trifluoromethylphenylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[5-(5-Methylpyridin-2-ylamino)-pyridin-2-yl]phenyl}-cyclohexyl)-aceticacid,(4-{4-[5-(5-Trifluoromethylpyridin-2-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid methyl ester,(4-{4-[5-(5-Chloropyridin-2-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[5-(6-Methoxypyridin-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[5-(5-Fluoropyridin-2-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[5-(6-Acetylaminopyridin-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,{4-[4-(3-Methoxy-5-phenylamino-pyridin-2-yl)-phenyl]-cyclohexyl}-aceticacid,{4-[4-(3-Methoxy-5-(3-fluorophenyl)amino-pyridin-2-yl)-phenyl]-cyclohexyl}-aceticacid,{4-[4-(3-Methoxy-5-(4-trifluoromethyl-phenyl)amino-pyridin-2-yl)-phenyl}-cyclohexyl}-aceticacid,{4-[4-(3-Methoxy-5-(3-chlorophenyl)amino-pyridin-2-yl)-phenyl]-cyclohexyl}-aceticacid,(4-{4-[5-(3-Fluoro-phenylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[5-(3-Chloro-phenylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[5-(1-Methyl-1H-pyrazol-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[5-(5-Fluoro-6-methoxy-pyridin-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[5-(Isoxazol-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[6-(3-Chloro-phenylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[6-(3-Fluoro-phenylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-aceticacid, {4-[4-(6-m-Tolylamino-pyridazin-3-yl)-phenyl]-cyclohexyl}-aceticacid,(4-{4-[6-(3-Trifluoromethyl-phenylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[6-(3-Methoxy-phenylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[6-(3-Cyano-phenylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[6-(2-Fluoro-phenylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[6-(4-Chloro-phenylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-aceticacid, {4-[4-(6-p-Tolylamino-pyridazin-3-yl)-phenyl]-cyclohexyl}-aceticacid,(4-{4-[6-(4-Trifluoromethyl-phenylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[6-(3-Chloro-4-methoxy-phenylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[6-(3-Chloro-2-methyl-phenylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-aceticacid, {4-[4-(6-Phenylamino-pyridazin-3-yl)-phenyl]-cyclohexyl}-aceticacid,(4-{4-[6-(3-Chloro-2-methoxy-phenylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[6-(2-Methoxy-phenylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[6-(4-Methoxy-phenylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[6-(6-Trifluoromethyl-pyridin-3-ylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[6-(4-Trifluoromethoxy-phenylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[6-(4-Fluoro-phenylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[6-(6-Amino-pyridin-3-ylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[6-(Methyl-m-tolyl-amino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-aceticacid,[4-(4-{6-[(3-Chloro-phenyl)-methyl-amino]-pyridazin-3-yl}-phenyl)-cyclohexyl]-aceticacid,[4-(4-{6-[(3-Methoxy-phenyl)-methyl-amino]-pyridazin-3-yl}-phenyl)-cyclohexyl]-aceticacid,(4-{4-[6-(2-Methyl-6-trifluoromethyl-pyridin-3-ylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[6-(3-Chloro-2-methoxy-phenylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-aceticacid,(1S,2R)-2-{4-[6-(3-Chloro-phenylamino)-pyridazin-3-yl]-benzoylamino}-cyclohexanecarboxylicacid,4-{4-[6-(3-Trifluoromethyl-phenylamino)-pyridazin-3-yl]-phenyl}-cyclohexanecarboxylicacid,2-(4-{4-[6-(3-Chloro-phenylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-acetamide,(6-{4-[4-(2H-Tetrazol-5-ylmethyl)-cyclohexyl]-phenyl}-pyridazin-3-yl)-(6-trifluoromethyl-pyridin-3-yl)-amine,3-(4-{4-[6-(6-Trifluoromethyl-pyridin-3-ylamino)-pyridazin-3-yl]-phenyl}-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one,(4-{4-[4-Methyl-6-(6-trifluoromethyl-pyridin-3-ylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[4-Methyl-6-(4-trifluoromethyl-phenylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-aceticacid(4-{4-[5-(6-Trifluoromethyl-pyridin-3-ylamino)-pyrazin-2-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[5-(2,2-Dimethyl-propionylamino)-pyridin-2-yl]phenyl}-cyclohexyl)-aceticacid,(4-{4-[5-(Benzooxazol-2-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[6-(6-Methoxy-pyridin-3-ylamino)-5-methyl-pyridin-3-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[5-Fluoro-6-(6-methoxy-pyridin-3-ylamino)-pyridin-3-yl]-phenyl}-cyclohexyl)-aceticacid,Oxo-(4-{4-[6-(6-trifluoromethyl-pyridin-3-ylamino)-pyridin-3-yl]-phenyl}-cyclohexyl)-aceticacid, {4-[4-(5-Acetylamino-pyridin-2-yl)-phenyl]-cyclohexyl}-aceticacid,(4-{4-[5-(3-Trifluoromethyl-benzoylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,[4-(4-{5-[(Pyridine-2-carbonyl)-amino]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid,[4-(4-{5-[3-(4-Trifluoromethoxy-phenyl)-ureido]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid,[4-(4-{5-[3-(2-Trifluoromethyl-phenyl)-ureido]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid,(4-{4-[5-(3-o-Tolyl-ureido)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,[4-(4-{5-[(1-Methyl-1H-indole-3-carbonyl)-amino]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid,[4-(4-{5-[(1H-Indole-3-carbonyl)-amino]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid,[4-(4-{5-[(Pyridine-3-carbonyl)-amino]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid,[4-(4-{5-[(6-Methyl-pyridine-3-carbonyl)-amino]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid,[4-(4-{5-[(5-Bromo-pyridine-3-carbonyl)-amino]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid,[4-(4-{5-[(5-Chloro-6-methoxy-pyridine-3-carbonyl)-amino]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid,[4-(4-{5-[(5-Isobutyl-isoxazole-3-carbonyl)-amino]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid,[4-(4-{5-[(3-tert-Butyl-1-methyl-1H-pyrazole-4-carbonyl)-amino]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid,[4-(4-{5-[(5-tert-Butyl-1H-pyrazole-3-carbonyl)-amino]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid,[4-(4-{5-[(5-Isopropyl-isoxazole-3-carbonyl)-amino]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid,{4-[4-(5-Isobutoxycarbonylamino-pyridin-2-yl)-phenyl]-cyclohexyl}-aceticacid,[4-(4-{5-[((S)-5-Oxo-pyrrolidine-2-carbonyl)-amino]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid,(4-{4-[5-(4-Fluoro-3-trifluoromethyl-benzoylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[5-(4-Trifluoromethyl-benzoylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,[4-(4-{5-[(6-Trifluoromethyl-pyridine-3-carbonyl)-amino]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid,(4-{4-[5-(3-Fluoro-5-trifluoromethyl-benzoylamino)-pyridin-2-yl]phenyl}-cyclohexyl)-aceticacid,[4-(4-{5-[(Tetrahydro-pyran-4-carbonyl)-amino]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid,[4-(4-{5-[(5-Bromo-2-methoxy-pyridine-3-carbonyl)-amino]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid,[4-(4-{5-[(1,5-Dimethyl-1H-pyrazole-3-carbonyl)-amino]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid,[4-(4-{5-[(5-Methoxy-1H-indole-3-carbonyl)-amino]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid,[4-(4-{5-[(2,5-Dimethyl-1H-pyrrole-3-carbonyl)-amino]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid,[4-(4-{5-[(1-Methyl-5-trifluoromethyl-1H-pyrazole-4-carbonyl)-amino]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid,{4-[4-(5-{[4-(Morpholine-4-sulfonyl)-1H-pyrrole-2-carbonyl]-amino}-pyridin-2-yl)-phenyl]-cyclohexyl}-aceticacid,(4-{4-[5-(2-Fluoro-2-methyl-propionylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,[4-(4-{5-[(1-Methyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl)-amino]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid methyl ester,(4-{4-[5-(2-Methyl-2-pyrazol-1-yl-propionylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,[4-(4-{5-[(5-Isopropyl-isoxazole-4-carbonyl)-amino]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid,[4-(4-{5-[(1-Methyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl)-amino]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid,[4-(4-{5-[(5-Cyclopropyl-isoxazole-4-carbonyl)-amino]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid,[4-(4-{5-[(5-Cyclopropyl-isoxazole-4-carbonyl)-amino]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid methyl ester,[4-(4-{5-[(5-Cyclopropyl-isoxazole-3-carbonyl)-amino]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid,[4-(4-{5-[(6-Methoxy-pyridine-3-carbonyl)-amino]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid,(4-{4-[5-(2,2-Dimethyl-butyrylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[5-(2-Methoxy-2-methyl-propionylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,[4-(4-{5-[(1,5-Dimethyl-1H-pyrazole-4-carbonyl)-amino]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid,(4-{4-[5-(Tetrahydro-pyran-4-yloxycarbonylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,{4-[4-(5-Cyclopropylmethoxycarbonylamino-pyridin-2-yl)-phenyl]-cyclohexyl}-aceticacid,(4-{4-[5-(Tetrahydro-furan-2-ylmethoxycarbonylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[5-(Tetrahydro-pyran-2-ylmethoxycarbonylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[5-(3-Methyl-oxetan-3-ylmethoxycarbonylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[5-(Tetrahydro-pyran-4-ylmethoxycarbonylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[5-(2-Methyl-pyridin-3-ylmethoxycarbonylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,[4-(4-{5-[3-(4-Chloro-3-trifluoromethyl-phenyl)-ureido]-pyridin-2-yl}-phenyl)-cyclohexyl]-aceticacid,{4-[4-(5-Isopropylcarbamoyl-pyridin-2-yl)-phenyl]-cyclohexyl}-aceticacid, {4-[4-(6-Carbamoyl-pyridin-2-yl)-phenyl]-cyclohexyl}-acetic acid,{4-[4-(6-Isopropylcarbamoyl-pyridin-2-yl)-phenyl]-cyclohexyl}-aceticacid,(4-{4-[5-(6-Trifluoromethyl-pyridin-3-ylcarbamoyl)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[5-(4-Trifluoromethyl-benzenesulfonylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[5-(3-Trifluoromethyl-benzenesulfonylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[5-(1,2-Dimethyl-1H-imidazole-4-sulfonylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[5-(5-Fluoro-pyridin-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[5-(6-Isopropoxy-pyridin-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[5-(5-Bromo-pyridin-2-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[5-(2-Methoxy-pyrimidin-5-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[5-(6-Methylsulfanyl-pyridin-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[5-([1,2,4]Triazin-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[5-(2-Dimethylamino-pyrimidin-5-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[5-(5-Methylsulfanyl-pyridin-2-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[5-(3,5-Difluoro-pyridin-2-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[5-(6-Trifluoromethyl-pyridin-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid methyl ester,(4-{4-[5-(5-Chloro-6-methoxy-pyridin-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[5-(5-Fluoro-4-methyl-pyridin-2-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[5-(3-Chloro-5-methyl-pyridin-2-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[5-(5-Difluoromethyl-6-methoxy-pyridin-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[5-(5-Methanesulfonyl-pyridin-2-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[3-Fluoro-5-(6-trifluoromethyl-pyridin-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[5-(1H-Benzoimidazol-2-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[5-(5-Trifluoromethyl-[1,3,4]oxadiazol-2-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[5-(6-Methyl-benzooxazol-2-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[5-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[5-(6-Chloro-benzooxazol-2-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid methyl ester,(4-{4-[5-(6-Chloro-benzooxazol-2-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[5-(5-Chloro-6-methoxy-benzooxazol-2-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[5-(5-tert-Butyl-[1,3,4]oxadiazol-2-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[2-(6-Trifluoromethyl-pyridin-3-ylamino)-pyrimidin-5-yl]-phenyl}-cyclohexyl)-aceticacid,(4-{4-[2-(5-Chloro-pyridin-2-ylamino)-pyrimidin-5-yl]-phenyl}-cyclohexyl)-aceticacid(4-{4-[6-(2-Methyl-6-trifluoromethyl-pyridin-3-ylamino)-pyridin-3-yl]-phenyl}-cyclohexyl)-aceticacid, or a pharmaceutically acceptable salt thereof.
 52. Apharmaceutical composition, comprising: the compound according to claim38, and a pharmaceutical acceptable carrier or excipient.
 53. A methodfor treating conditions or disorders associated with DGAT1 activity,comprising: administering to a subject a compound having the followingstructureA-L1-B-C-D-L2-E wherein: A is a substituted or unsubstituted alkyl,cycloalkyl, aryl, or heterocyclyl group, L1 is selected from the groupconsisting of: an amine group —NH— a substituted amine group of theformula —N(CH₃)—, —CH₂—NH— or —CH₂—CH₂—NH—, an amide group —C(O)—NH—, asulphonamide group —S(O)₂—NH—, or a urea group —NHC(O)—NH—, B is asubstituted or unsubstituted, monocyclic, 5- or 6-membered divalentheteroaryl group, C-D is selected from the following cyclic structures:C-D together is a substituted or unsubstituted divalent biphenyl group,C is a substituted or unsubstituted divalent phenyl group and D is asingle bond, C is a substituted or unsubstituted divalent phenyl group,and D is a substituted or unsubstituted divalent non-aromatic monocyclicring which is selected from a saturated or unsaturated divalentcycloalkyl group or a saturated or unsaturated divalent heterocycloalkylgroup, C-D together is a spiro residue, wherein the first cycliccomponent is a benzo-fused cyclic component wherein the ring which isfused to the phenyl part is a 5- or 6-membered ring, optionallycomprising one or more heteroatoms, the first cyclic component beingattached to the moiety B via its phenyl part, and the second cycliccomponent is a cycloalkyl or cycloalkylidenyl residue which is attachedto L2, L2 is selected from the group consisting of: a single bond, adivalent residue having the following structure:—[R¹]_(a)—[R²]_(b)—[C(O)]_(c)—[N(R³)]_(d)—[R⁴]_(e)—[R⁵]_(f)— wherein ais 0 or 1, b is 0 or 1, c is 0 or 1, d is 0 or 1, e is 0 or 1, f is 0 or1, with the proviso that (a+b+c+d+e+f)>0, and c=1 if d=1, R¹, R², R⁴ andR⁵, which can be the same or different, are a substituted orunsubstituted divalent alkyl, cycloalkyl, alkenyl, alkynyl, alkylene,aryl or heterocyclyl residue, R³ is H or hydrocarbyl, or R³ and R⁴ formtogether with the nitrogen atom to which they are attached a 5- or6-membered heterocycloalkyl group, an alkylidenyl group which is linkedto the moiety D via a double bond, with the proviso that L2 is not—C(O)—[R⁴]—[R⁵]_(f)— when C is a substituted or unsubstituted divalentphenyl group and D is a single bond, E is selected from the groupconsisting of: a sulphonic acid group and derivatives thereof, acarboxyl group and derivatives thereof, wherein the carboxyl carbon atomis attached to L2, a phosphonic acid group and derivatives thereof, analpha-keto hydroxyalkyl group, a hydroxyalkyl group wherein the carbonatom bonded to the hydroxyl group is further substituted with one or twotrifluormethyl groups, a substituted or non-substituted five-memberedheterocyclyl residue having in the ring at least two heteroatoms and atleast one carbon atom, wherein the at least one carbon atom of the ringis bonded to two heteroatoms; at least one of the heteroatoms to whichthe carbon atom of the ring is bonded is a member of the ring; and atleast one of the heteroatoms to which the carbon atom of the ring isbonded or at least one of the heteroatoms of the ring is bearing ahydrogen atom; or a prodrug or a pharmaceutically acceptable saltthereof.
 54. A pharmaceutical compositions comprising: i) a compoundaccording to claim 38, ii) at least one compound selected from a)antidiabetic agents, b) hypolipidemic agents, c) anti-obesity agents, d)anti-hypertensive agents, e) agonists of peroxisomeproliferator-activator receptors, and iii) one or more pharmaceuticallyacceptable carriers.
 55. A method for treating conditions or disordersassociated with DGAT1 activity, comprising: administering to a mammal inneed thereof a therapeutically effective amount of a compound of claim38.
 56. The method according to claim 55, wherein the disorder isselected from a metabolic disorders such as obesity, diabetes, anorexianervosa, bulimia, cachexia, syndrome X, insulin resistance,hypoglycemia, hyperglycemia, hyperuricemia, hyperinsulinemia,hypercholesterolemia, hyperlipidemia, dyslipidemia, mixed dyslipidemia,hypertriglyceridemia, and nonalcoholic fatty liver disease;cardiovascular diseases, such as atherosclerosis, arteriosclerosis,acute heart failure, congestive heart failure, coronary artery disease,cardiomyopathy, myocardial infarction, angina pectoris, hypertension,hypotension, stroke, ischemia, ischemic reperfusion injury, aneurysm,restenosis, and vascular stenosis; neoplastic diseases, such as solidtumors, skin cancer, melanoma, lymphoma, and endothelial cancers, forexample, breast cancer, lung cancer, colorectal cancer, stomach cancer,other cancers of the gastrointestinal tract (for example, esophagealcancer and pancreatic cancer), prostate cancer, kidney cancer, livercancer, bladder cancer, cervical cancer, uterine cancer, testicularcancer, and ovarian cancer; dermatological conditions, such as acnevulgaris. In yet another aspect, the present invention provides methodsof using a compound or composition of the invention as an anorectic.